Bleeding prophylaxis for major surgery in patients with type 2 von Willebrand disease with an intermediate purity factor VIII-von Willebrand factor concentrate (Haemate-P).

The parameters to diagnose von Willebrand disease (vWD) include factor VIII coagulant activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor activity (vWF:RCo), and von Willebrand factor collagen binding activity (vWF:CB). Type 2 vWD is associated with a moderate bleeding diathesis due to low levels of vWF:RCo and vWF:CB as compared with near normal or normal values for FVIII:C and vWF:Ag. As the factor VIII/von Willebrand factor (vWF) concentrate, Haemate-P, is featured by a vWF:RCo/FVIII:C ratio of about 2.2, the recommended loading dose of 50 U/kg FVIII:C followed by 25 U/kg FVIII:C every 12 h for several days for bleeding prophylaxis in type 2 vWD patients undergoing major surgery demonstrated a predicted significant over-treatment reaching vWF:RCo levels above 2 U/ml. Therefore, we restricted Haemate-P substitution for major surgery to one loading dose of 40-50 U/kg FVIII:C (88-110 U/kg vWF:RCo) followed by 15-20 U/kg FVIII:C (33-44 U/kg vWF:RCo) every 12 h for several days and evaluated this strategy in a prospective pharmacokinetic and efficacy study for bleeding prophylaxis in five type 2 vWD patients. Pre-treatment and peak levels (1 h after Haemate-P loading dose) rose from 0.43-0.66 to 1.5-2.5 U/ml for FVIII:C, from 0.23-0.45 to 1.5-2.5 U/ml for vWF:Ag, from 0.10-< 0.20 to 1.5-2.5 U/ml for vWF:RCo, and from < 0.05-0.10 to 1.0-2.0 U/ml for vWF:CB. Mean in vivo recoveries per transfused IU FVIII:C/kg body weight were 3.2% for FVIII:C, 3.9% for vWF:RCo, and 2.8% for vWF:CB. Mean in vivo recoveries per transfused IU vWF:RCo/kg were 1.45% for FVIII:C, 1.7% for vWF:RCo and 1.25% for vWF:CB. The biological half-life times after transfused Haemate-P were about 12 h for both vWF:RCo and vWF:CB. Based on these pharmacokinetic data, we propose to adapt the loading dose factor VIII/vWF concentrate (Haemate-P) to 60-80 U/kg vWF:RCo followed by 30-40 U/kg vWF:RCo every 12 h for no longer than several days (less than 1 week) for bleeding prophylaxis during major surgery or trauma, and to one loading dose of 40-60 U/kg vWF:RCo for minor surgery, trauma or mucotaneous bleedings in patients with type 2 vWD unresponsive to DDAVP.     

Guidelines for the evaluation of intravenous desmopressin and von Willebrand factor/factor VIII concentrate in the treatment and prophylaxis of bleedings in von Willebrand disease types 1, 2, and 3

The current standard for the diagnosis and management of patients with congenital von Willebrand disease (vWD) includes bleeding times (BTs), PFA-100 closure time (PFA-CT), factor (F) VIII:coagulant activity (C), vWF:antigen (Ag), vWF:ristocetin cofactor activity (RCo), a sensitive vWF:collagen-binding activity (CB), ristocetin-induced platelet aggregation (RIPA), analysis of vWF multimers in low- and high-resolution agarose gels, and the response to desmopressin. Guidelines and recommendations for prophylaxis and treatment of bleedings in vWD patients with vWF/FVIII concentrates should be derived from analysis of the content of these concentrates and from pharmacokinetic studies in different types of vWD patients with severe type 1, 2, or 3 vWD. The vWF/FVIII concentrates should be characterized by labeling with FVIII:C, vWF:RCo, vWF:CB, and vWF multimeric pattern, which will determine their predicted efficacy and safety in prospective management studies. Because the bleeding tendency is moderate in type 2 and severe in type 3 vWD, and because the FVIII:C levels are subnormal in type 2 and very low in type 3 vWD patients, new guidelines using vWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are proposed. Such guidelines should be stratified for the severity of bleeding, the type of surgery (either minor or major), and also for the severity and type of vWD (i.e., either type 2 or 3 vWD).     

Hyper-responsiveness to DDAVP for patients with type I von Willebrand's disease and normal intra-platelet von Willebrand factor

Desmopressin (DDAVP) has gained wide acceptance as the drug of first choice in the treatment or prevention of haemorrhages in the majority of patients with von Willebrand's disease (vWd). However, data concerning the clinical effectiveness of DDAVP refer generally to mild vWd, with factor VIII and vW factor levels usually above 20% of normal. In 14 patients with type I vWd characterized by very low plasma levels of factor VIII coagulant activity (VIII:C) and vWf, measured as ristocetin cofactor activity (lower than 20% and 3% of normal respectively), but with a normal intraplatelet content of vWf, a test infusion of DDAVP (0.4 microgram/kg) elicited a very marked increase of VIII:C and vWf and normalized the bleeding time. All these patients subsequently underwent tooth extraction after DDAVP infusion. The incidence of bleeding was remarkably low, with only two minor late bleeding episodes easily stopped by repeating DDAVP infusion. Compared to the cases of type I vWd with unknown intraplatelet vWf content reported in the literature, this subgroup of patients had a more marked, albeit short-lived, increment of VIII:C and vWf.     

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 ≈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) [ t _1/2: 16.9 h]; 0.061 (h⁻¹) [ t _1/2: 11.3 h] and 0.006 (h⁻¹) [ t _1/2: 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⁻¹h⁻¹ and the decay rate 0.043 (h⁻¹) [ t _1/2: 16.1 h]. The rate of decay for RCoF and vWF:Ag were 0.050 (h⁻¹) [ t _1/2: 13.9 h] and 0.044 (h⁻¹) [ t _1/2: 15.7 h], respectively.     

Reduced von Willebrand factor survival in type Vicenza von Willebrand disease.

Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype.     

Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease

In a normal population, VWF plasma levels (VWF:Ag) and VWF activity (VWF:RCo) increase by approximately 0.17 and 0.15 IU mL^?1 per decade, but the influence of age is unknown in patients with type 1 von Willebrand disease (VWD). In a retrospective cohort study, the medical records of 31 type 1 VWD patients over the age of 30, who had been followed for ≥5 years, were reviewed for baseline clinical data and previously performed VWF:Ag, VWF:RCo and factor VIII levels (FVIII:C). VWF multimer analysis was normal in 28/31 cases performed. Mean age at diagnosis was 33 (range 16–60 years), and duration of follow‐up ranged from 5 to 26 years (mean 11 years). Patients had 2–10 time points of VWD testing (mean of 5.2). The mean VWF:Ag, VWF:RCo and FVIII:C at time of diagnosis were 0.44 IU mL^?1 0.34 IU mL^?1 and 0.75 IU mL^?1. At last follow‐up, the mean VWF:Ag, VWF:RCo and FVIII:C were significantly increased to 0.71 IU L^?1, 0.56 IU mL^?1 and 0.90 IU mL^?1 (P ≤ 0.001, <0.001, and 0.0081 respectively). Here 18/31 patients had VWF:Ag, VWF:RCo and FVIII: C levels that increased into the normal range. The rate of change in VWF:Ag, VWF:RCo and FVIII was 0.30 IU mL^?1 (0.21–0.39, CI 95%, P < 0.0001), 0.20 IU mL^?1 per decade (0.13–0.27, CI 95%, P = 0.0001) and 0.20 IU mL^?1 (0.11–0.29, CI 95%, P = 0.0011). Patients with type 1 VWD experience age‐related increases to VWF:Ag and VWF:RCo which can result in normalization of VWF levels. Further studies are required to determine if the bleeding phenotype resolves with the increases in VWF:Ag and VWF:RCo levels.     

Inverse relationship between plasma von Willebrand factor and soluble P selectin in patients with type 1 but not type 2 von Willebrand disease

P selectin is a component of endothelial Wiebel-Palade body membrane and platelet alpha granule membrane. Patients with von Willebrand disease (VWD) have low plasma von Willebrand factor (VWF). To examine the relationship between plasma P selectin and VWF, both were measured by ELISA in 38 patients with VWD and 40 controls. The patient had lower VWF (P < 0.001) but similar P selectin levels (P = 0.458). In 24 type 1 VWD patients, VWF and P selectin correlated inversely (P = 0.005) but in 14 type 2 VWD patients there was no correlation (P = 0.997). These data imply major differences in VWF/P-selectin regulation between types 1 and 2 VWD.     

Response of von Willebrand factor parameters to desmopressin in patients with type 1 and type 2 congenital von Willebrand disease: diagnostic and therapeutic implications

In the present study, we prospectively evaluated the contribution of the von Willebrand factor collagen-binding activity (vWF:CBA) assay, vWF multimeric analysis, and the response to intravenous desmopressin (DDAVP) to correctly diagnose and classify congenital von Willebrand disease (CvWD) in 24 probands with mild to moderate type 1 vWD, 6 probands with severe CvWD type 1, and 12 probands with type 2 CvWD. CvWD type 1 of mild to moderate severity is featured by proportionally decreased levels of vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCof), and vWF:CBA between 0.20 and 0.60 u/mL and a normal response to DDAVP of factor (F) VIIIc and all vWF parameters. Severe type 1 CvWD with vWF parameters below 0.10 or 0.20 u/mL is associated with a decreased response to DDAVP of all vWF parameters, indicating a defective synthesis or secretion vWF by endothelial cells, or both. CvWD 2M may present as severe type 1 CvWD, as type 1 "platelet-discordant" CvWD, or with the combination of a discrepant vWF:RCof/Ag ratio and the presence of all vWF multimers. Ristocetin-induced platelet aggregation (RIPA) is normal in type 1 CvWD. CvWD 2M is typically featured by decreased RIPA, normal or near normal vWF multimers, and no or only a poor response to DDAVP of vWF:RCof as compared with a fairly good response to DDAVP of vWF:Ag and vWF:CBA. CvWD Vicenza is characterized by unusually large vWF multimers and very low levels of FVIIIc, vWF:Ag, and vWF:RCof. CvWD Vicenza differs from CvWD 2M because the vWF:RCof/Ag ratios are completely normal before and after DDAVP; the response to DDAVP is equally good for FVIIIc, vWF:Ag, vWF:RCof, and vWF:CBA and is followed by very short half-life times for FVIIIc and all vWF parameters. Pertinent findings in type 2A and 2B CvWD included prolonged Ivy bleeding time (BT), low vWF:RCof/Ag and vWF:CBA ratios, absence of the high vWF multimers, and, depending on the severity of the absence of intermediate vWF multimers, pronounced increase of low vWF multimers and vWF degradation products because of increased proteolysis of the high and intermediate vWF multimers. RIPA is normal in CvWD 2A and increased in CvWD 2B. The response to DDAVP in CvWD 2A is normal for FVIIIc and vWF:Ag but is transient with partial correction and short half-life times of vWF:CBA and vWF:RCof. DDAVP does not correct BT and multimeric patterns in CvWD type 2B, despite significant increase of vWF parameters. CvWD types 2C, 2D, and 2E are featured by very low functional vWF parameters, the presence of typically abnormal vWF multimers, a very poor response of vWF:CBA, a decreased response of vWF:RCof, and a fairly good response of vWF:Ag to DDAVP with no correction of prolonged Ivy BT and no correction of the vWF multimeric pattern as the consequence of a multimerization or dimerization defect of the vWF molecules. CvWD type 2N usually presents with much lower levels for FVIIIc as compared with vWF, normal Ivy BT, and normal vWF multimeric pattern. The response to DDAVP is normal for all vWF parameters but is decreased for FVIIIc with shortened half-life times.     

Successful treatment of patients with von Willebrand disease using a high-purity double-virus inactivated factor VIII/von Willebrand factor concentrate (Immunate)

Fourteen patients with different types of von Willebrand disease (vWD) having acute bleeds or elective surgery were treated with Immunate(sound recording copyright sign), a double-virus inactivated factor VIII/von Willebrand factor (FVIII/vWF) concentrate. The concentrate was applied as a bolus or via continuous infusion. FVIII activity (FVIIIc), vWF antigen (vWF:Ag), ristocetin cofactor activity (vWF:RCo), collagen binding activity (vWF:CB), activated partial thromboplastin time (aPTT), and von Willebrand multimers (vW-multimers) were monitored for 48 hours. Pharmacokinetic analyses were performed. The clinical efficacy was rated excellent or good. Bleeding complications occurred in 3 patients due to an additional FXIII deficiency in one patient, to a surgically induced bleed in another patient, and a rather short substitution period in the third patient. There were no serious adverse experiences. One patient showed a phlebitic reaction at the site of venous access after more than 100 hours of continuous infusion, requiring a change to application via bolus.     

Significant linkage and non-linkage of type 1 von Willebrand disease to the von Willebrand factor gene

Significant linkage of types 2A and 2B von Willebrand disease (VWD) to the von Willebrand factor (VWF) gene have been reported, as well as mutations in the VWF gene. However, data for the partial quantitative variant are less consistent. An inconsistency of association between the type 1 VWD phenotype and genotype has been reported recently. We undertook linkage analysis of 12 families with definite or possible type 1 VWD patients. One family with classic type 1 VWD had a high lod score (Z = 5.28, theta = 0.00). A total lod score of 10.68 was obtained for the four families with fully penetrant disease. In two families linkage was rejected, while three families did not show conclusive evidence of linkage. This study corroborates ABO blood group influence, especially in patients with mild deficiencies and/or incomplete penetrance. Indirect genetic analysis may be an option for diagnosing asymptomatic or presymptomatic type 1 VWD carriers, particularly in families showing higher penetrance. The study indicates defects of the VWF locus are to be expected in more than half of the families studied. However, as defects at different loci may be the cause of this phenotype, the results of the segregation analyses should be interpreted with caution, especially in studies involving small families, or mild expressions of the disorder or incomplete penetrance.     

Long-term prophylaxis with intermediate-purity factor VIII concentrate (Haemate P) in a patient with type 3 von Willebrand disease and recurrent gastrointestinal bleeding

Prophylaxis with von Willebrand factor (VWF)-containing concentrates is considered to be a potential approach for patients with von Willebrand disease (VWD) and severe bleeding tendency. We report the case of a 57-year-old man with type 3 VWD and a history of recurrent melaena. Bleeding frequency and severity had progressively increased and the patient showed chronic anaemia and persistent haemoglobin in the stools. Endoscopic examinations revealed multiple vascular mucosal abnormalities (MVA) of the stomach and large bowel. Photocoagulation of some actively bleeding lesions and octreotide did not significantly affect his clinical conditions: six red cell transfusions and >400 000 IU of intermediate-purity factor VIII (FVIII) concentrate (Haemate P) on-demand were needed during 2002. Prophylaxis with Haemate P 40 IU kg(-1) (102 IU kg(-1) VWF:RCo) thrice weekly was associated with improvement of his mean haemoglobin levels, cessation of clear-cut melaena and red cell transfusions and reduction of total Haemate P requirements (-20% over 2003-04). Prophylaxis with Haemate P is still ongoing without any adverse event over a 30-month period. Clinical course and pharmacokinetic evaluations led to administer Haemate P each 72-96 h. Possible vascular complications were excluded by a careful clinical follow up, as the patient suffered from arterial hypertension and diabetes mellitus; thrombophilic abnormalities were previously excluded and no signs of abnormal coagulation activation or FVIII:C levels >150% were detected thereafter. Long-term prophylaxis with Haemate P has been shown to be safe, effective (also in terms of quality of life) and cost saving in this patient with severe gastrointestinal bleeding due to MVA and VWD.     

Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis

The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0–21 days (median 6). VWF levels peaked at 250% of baseline – 4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment.     

Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor

No defects have been reported in moderately severe type 1 von Willebrand disease (vWD) with a clear autosomal dominant inheritance pattern, and the mechanism underlying this form of vWD remains obscure. We have studied a type 1 vWD family with such a dominant phenotype. The entire coding sequence of the von Willebrand factor (vWF) gene was analyzed by direct sequencing of DNA fragments amplified by polymerase chain reaction. Only one candidate mutation T(3445)-->C in exon 26 was detected that predicts a replacement of cysteine (C) at position 386 of the mature vWF subunit by arginine (R). Both mutant and normal vWF alleles were expressed as shown by analysis of platelet mRNA. This substitution segregates with vWD in the family and was not found in 100 unrelated individuals. The recombinant mutant vWF(C386R) was characterized by expression in 293T cells. The secretion of vWF(C386R) was greatly impaired due to retention in the endoplasmic reticulum. In cotransfections of normal and mutant vWF constructs, the vWF(C386R) subunits caused a dose-dependent decrease in the secretion of vWF. The multimer pattern remained nearly normal and consistent with a dominant vWD type 1 phenotype. The importance of the cysteine residues in the D3 domain of vWF in the pathogenesis of dominant type 1 vWD was further shown by the detection of another cysteine mutation, Cys367-->Phe, in two additional unrelated patients with a similar dominant type 1 vWD phenotype. We conclude that the loss of cysteine pairing in the D3 domain, leaving one free cysteine, can induce a purely quantitative deficiency of vWF by dominantly suppressing the secretion of normal vWF.     

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study.

Among 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.     

Von Willebrand factor propeptide makes it easy to identify the shorter Von Willebrand factor survival in patients with type 1 and type Vicenza von Willebrand disease

Reduced von Willebrand factor (VWF) half-life has been suggested as a new pathogenic mechanism in von Willebrand disease (VWD). The usefulness of VWF propeptide (VWFpp) in exploring VWF half-life was assessed in 22 type 1 and 14 type Vicenza VWD patients, and in 30 normal subjects, by comparing the findings on post-Desmopressin (DDAVP) VWF t(1/2) elimination (t(1/2el)). The VWFpp/VWF antigen ratio (VWFpp ratio) was dramatically increased in type Vicenza VWD (13.02 +/- 0.49) when compared to normal subjects (1.45 +/- 0.06), whereas it appeared to be normal in all type 1 VWD patients (1.56 +/- 0.7), except for the four carrying the C1130F mutation (4.69 +/- 0.67). A very short VWF t(1/2el) was found in type Vicenza VWD (1.3 +/- 0.2 h), while all type 1 VWD patients had a t(1/2el) similar to that of the controls (11.6 +/- 1.4 and 15.4 +/- 2.5 h respectively), except for the four patients carrying the C1130F mutation, who had a significantly shorter VWF survival (4.1 +/- 0.2 h). A significant inverse correlation emerged between VWFpp ratio and VWF t(1/2el) in both VWD patients and normal subjects. The VWFpp ratio thus seemed very useful for distinguishing between type 1 VWD cases with a normal and a reduced VWF survival, as well as for identifying type Vicenza VWD.     

Treatment and prevention of acute bleedings in von Willebrand disease – efficacy and safety of Wilate®, a new generation von Willebrand factor/factor VIII concentrate

Summary.  For many patients with von Willebrand disease (VWD), the replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is the treatment of choice. To evaluate clinical efficacy, safety and tolerability of Wilate^®, an albumin-free VWF/FVIII concentrate with a ratio of the two haemostatic moieties of approximately 1 to 1, a prospective clinical programme has been designed. The dataset on the treatment and prevention of bleedings is derived from 44 patients (20 males and 24 females) of all VWD types. Thousand and ninety five bleeding episodes were treated with an overall efficacy rating of excellent or good in 96%. The median dose per treatment day was 26 IU FVIII:C per kg. Eighty-one per cent of bleeds were stopped within 1 or 2 days. Gastrointestinal (GI) bleeds needed higher doses (mean 44 IU kg⁻¹) and longer treatment (mean 4 days). Efficacy and dosing data from eight children of 12 or less years of age did not differ significantly from the overall study population. Nineteen patients, including six children, were treated prophylactically for more than 3 months (mean 14.8, range 3–46) with a mean prophylactic dose of 27.4 IU kg⁻¹ and a mean frequency of 1.9 infusions per week. A drop of bleeding frequency from a mean of 4.5 to 1.4 bleeds per month was observed. The overall tolerability was very good. Adverse drug reactions were rare and were mild or moderate in their intensity. The large prospective clinical dataset shows that Wilate^® is efficacious and safe in the treatment and prevention of haemorrhages in all VWD types in both adult and paediatric patients.     

Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease

Genetic studies were performed in two unrelated patients with the IIC phenotype of von Willebrand disease (vWD) characterized by the increased concentration of the protomeric form of von Willebrand factor (vWF). In patient B, the sequencing of both exons 15 and 16 of the vWF gene showed two sequence alterations: a 3-bp insertion in exon 15 resulting in the insertion of a Glycine at position 625 (625insGly) and a 2-bp deletion in exon 16 leading to a premature translational stop at codon 711 (711 ter), at the heterozygote state. Patient A was found homozygous for a single point mutation also localized in exon 15 and responsible for the substitution Cys623Trp. These candidate mutations were not found in a panel of 96 normal chromosomes, suggesting a causal relationship with IIC vWD phenotypic expression. The composite heterozygote or homozygote state of both patients supports the recessive mode of inheritance already described for this phenotype. Furthermore, the localization of these gene defects in the D2 domain of vWF propeptide, known to play an important role in vWF multimerization, provides another argument in favor of their causative effect regarding the peculiar multimeric pattern of vWF in these patients.