Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN)

The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF‐containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed‐rank test of differences in the medians was used. Sixty‐one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious.     

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.     

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.     

Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand’s disease (VWD) has limited value in dosing for surgery

Summary. Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate‐P^®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg^?1 VWF: RCo. Median plasma levels, half‐life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time‐concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL^?1 (range, 6–124); with a mean change from baseline >100 IU dL^?1 immediately after the infusion, decreasing to 10 IU dL^?1 at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL^?1 per IU kg^?1, for VWF:Ag 2.3 IU dL^?1 kg^?1 and for FVIII:C was 2.7 IU dL^?1 per IU kg^?1. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra‐individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri‐operative infusions.     

The impact of bleeding history,von Willebrand factor and PFA–100® on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM‐1VWD

The relationships between the Platelet Function Analyzer (PFA)‐100 and von Willebrand factor (VWF) levels and bleeding score (BS) were evaluated within a multicentre project on Molecular and Clinical Markers for the Diagnosis and Management of type 1 von Willebrand disease (MCMDM‐1VWD). PFA‐100 closure time, either with epinephrine (EPI) or adenosine diphosphate (ADP)‐cartridges, was measured in 107 index cases, 105 affected and 71 unaffected family members, and 79 healthy controls. By regression analysis VWF levels were strongly related to both closure times, with a non‐linear progression. In a multiple stepwise regression model, age‐ and sex‐adjusted PFA‐100 ADP and VWF ristocetin cofactor activity (VWF:RCo) were independently associated with BS. Most of the variation of BS was predicted by PFA‐100 ADP and VWF:RCo alone. In the subgroup of patients with subtle abnormalities of the multimeric pattern, VWF was invariably reduced and closure time prolonged in almost all of them. Neither PFA‐100 ADP nor EPI closure times appeared to significantly improve the diagnostic capability of VWF antigen (VWF:Ag) measurement. Thus, in an unselected population a normal PFA‐100 would be useful to exclude VWD, but whether it could replace the more specific VWF assay in patients with significant mucocutaneous bleeding symptoms remains to be investigated prospectively.     

von Willebrand factor/factor VIII concentrate (Humate‐P) for management of elective surgery in adults and children with von Willebrand disease

Summary. von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open‐label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate‐P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4‐point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half‐life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL^?1 per IU kg^?1 infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg^?1 (oral surgery) to 61.2 IU VWF:RCo kg^?1 (major surgery), with a median of 10 (range, 2–55) doses administered per subject. Adverse events considered possibly treatment‐related (n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD.     

Use of the collagen-binding assay for von Willebrand factor in the analysis of type 2M von Willebrand disease: a comparison with the ristocetin cofactor assay

This study compares the utility of two functional assays for von Willebrand factor (VWF), the ristocetin cofactor assay (VWF:RCo) and the collagen-binding assay (VWF:CBA). We analysed a group of 32 patients with type 2 von Willebrand disease (VWD) (25 patients with type 2M, six with type 2A and one with type 2B) and 22 normal control subjects. VWF:RCo/VWF antigen (VWF:Ag) ratios and VWF:CBA/VWF:Ag ratios were compared between the patient and control groups. In the six patients with type 2A VWD, both VWF:RCo/VWF:Ag ratios and VWF:CBA/VWF:Ag ratios were discordant (< or = 0.7). In the 25 type 2M VWD patients, the VWF:CBA/VWF:Ag ratios were concordant (> 0.7), but the VWF:RCo/VWF:CBA ratios were discordant (< or = 0.7) (P = 0.001) compared with control subjects. Thus, VWF:RCo/VWF:Ag ratios were discordant in both type 2M and 2A VWD patient groups indicating a functional abnormality. However, VWF:CBA/VWF:Ag ratios were discordant in the type 2A VWD group but not in the type 2M VWD group. Our study showed that VWF:CBA is sensitive to functional variants associated with the loss of high-molecular-weight multimers, i.e. type 2A and 2B in VWD, but the assay was unable to discriminate defective platelet-binding VWD variants with normal multimeric patterns such as type 2M VWD. It was concluded that the VWF:CBA assay should be used in association with rather than as a replacement for the VWF:RCo assay.     

Females with von Willebrand disease: 72 years as the silent majority

Summary. The monthly challenge of menstruation as well as the haemostatic challenge of childbirth post partum renders more females than males symptomatic with von Willebrand disease. Among vWD patients, the obstetrical and gynaecological morbidity is certainly more pronounced in Type 2,3 patients compared to Type 1 patients, but even in the latter group there is a high proportion of menorrhagia with associated anaemia, loss of time from work/school and the use of hysterectomy for ultimate control of bleeding. Despite the well known adage of the “gestational palliation” of vWD, there is a high proportion of postpartum haemorrhage in Type 1 patients also especially after the first 24 h after delivery. This may occur despite normalization of the factor VIIIc level in the third trimester, particularly in Type 2,3 patients. With the increasing availability of intranasal/subcutaneous DDAVP that could be readily administered at home for menorrhagia, there recently has been ongoing efforts internationally to determine the prevalence of vWD in females presenting with menorrhagia with a prevalence of 17% combined from two studies of 180 patients total. Issues remain regarding the optimal dose/schedule of intranasal/subcutaneous DDAVP for menorrhagia and the relative efficacy of antifibrinolytic agents. The proper role of oral contraceptives and danazol also deserves further study in vWd patients with menorrhagia. In sum, a comprehensive care approach in females with vWD is warranted analogous to the successful model of care of male haemophiliacs with the intent to (a) reduce unnecessary surgical interventions for menorrhagia, (b) improve the quality of life during menses and (c) optimize peri-partum management.     

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.     

Early transfusion of factor VIII/von Willebrand factor concentrates seems to be effective in the treatment of gatrointestinal bleeding in patients with von Willebrand type III disease

The association between gastrointestinal angiodysplasia and von Willebrand disease was reported 30 years ago. The clinical course of patients with von Willebrand disease and angiodysplasia is characterized by numerous admissions to hospital for gastrointestinal bleeding necessitating transfusion with packed red cells, factor VIII and plasma. The management of these patients is problematic. Numerous treatments for the gastrointestinal bleeding have been proposed: surgery, electrocoagulation, laser photocoagulation, sclerotherapy, arteriography with embolization, immunoglobulins, oestrogens, and octreotide, but no treatment modality has been successful in all cases. We report a 66-year-old-female with small bowel angiodysplasia and von Willebrand type III disease in whom prompt administration of factor VIII/vWF concentrates was effective. Education of patients to recognize minimal gastrointestinal bleeding manifestations, periodical clinical visits and early infusion of factor VIII/vWF seems to be fundamental for the success of this therapy. A longer follow-up and the study of other patients are needed to confirm our observation.     

Role for platelet von Willebrand factor in supporting platelet-vessel wall interactions in von Willebrand disease

Twelve infusions of plasma concentrates of von Willebrand factor (vWF) were given to four patients with severe (type III) von Willebrand disease (vWD). Their prolonged bleeding times were either completely or partially corrected after five infusions and had not changed after the remaining seven. In contrast, the low platelet coverage of the subendothelial surface of rabbit aorta perfused with normal washed platelets and red cells resuspended in preinfusion patient plasma was completely or partially corrected in ten instances by replacing preinfusion plasma with postinfusion plasma and remained unchanged in two. Postinfusion improvement in surface coverage was greater than that in bleeding time, suggesting that vWF from normal platelets is needed to support optimal platelet-vessel wall interactions in vWD. This possibility was further explored through other perfusion experiments. The subendothelial surface covered by platelets from an untreated patient with type III vWD (containing no measurable vWF) or from a type IIA vWD patient (containing dysfunctional vWF) resuspended in normal plasma was much smaller than that covered by normal platelets resuspended in normal plasma. These results establish that platelet vWF is important in supporting platelet-vessel wall interactions in vWD and also provide experimental support in favour of the therapeutic transfusion of normal platelets in addition to vWF concentrates to correct the bleeding time in vWD patients.     

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.     

Desmopressin and type II B von Willebrand disease

Summary. Type II B von Willebrand disease (vWD) is a rare subtype of vWD characterized by the presence of an abnormal von Willebrand factor (vWF) with enhanced affinity for the platelet membrane receptor glycoprotein Ib. The phenotypic hallmarks of the disease are represented by heightened ristocetin-induced platelet aggregation, occurring at very low ristocetin concentration, and the lack of high-molecular-weight vWF multimers in plasma. When infused with desmopressin, a variable degree of thrombocytopenia usually occurs in these patients, resulting from in vivo platelet aggregation caused by the release of abnormal vWF multimers from endogenous stores. We have reviewed the available literature data concerning the biological and clinical effects of desmopressin in the few cases so far reported. Despite the fear of thrombotic or haemorrhagic events, no significant side-effects have been reported also in the cases (70%) with severe thrombocytopenia. Moreover, the few clinical reports with the use of desmopressin in type II B patients showed a favourable effect in the prevention of bleeding during surgery or dental extraction. Thus, it appears that desmopressin could be safely used in selected clinical situations in patients with type II B vWD.     

Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients

Type 3 von Willebrand disease (VWD) is characterized by unmeasurable von Willebrand factor (VWF) levels in plasma and platelets and severe hemorrhagic symptoms. We have characterized at the molecular level a group of 40 patients (12 Italians, 14 Iranians, and 14 Indians) to evaluate genetic heterogeneity among these populations. Some of these patients have been previously investigated by us (mutations shown in italics); they are included in this study to provide a more comprehensive pattern of gene defects in type 3 VWD. Patients' DNA were first tested for more frequently reported mutations, then screened by single-strand conformation polymorphism and direct sequence analysis. Fifty gene defects were identified, of which 45 are novel. As expected most of these defects caused null alleles, 17 being nonsense mutations (Q218X, W222X, R365X, R373X, Y610X, W642X, E644X, Q706X, Q1311X, S1338X, Q1346X, Y1542X, R1659X, E1981X, E2129X, R2434X, and Q2544X), 12 small deletions (191delG, 276delT, 788del24, 2016del4, 2157delA, 2269delCT, 2435delC, 4092delAC, 6182delT, 7294delGT, 7683delT, and 8241del9), 4 small insertions (4414insC, 7130insC, 7137insT, and 7674insC), 8 possible splice site mutations (1110(-1)G-->A, 1946(-4)C-->T, 3108(+5)G-->A, 3379(+1)G-->A, 5053(+1)G-->A, 5170(+10)C-->T, 6977(-1)G-->C, and 7729(+7)C-->T), 8 candidate missense mutations (D47H, S85P, D141N, D141Y, C275S, C1071F, C2174G, and C2804Y), and 1 large gene deletion (exons 23-52). Only 2 of these patients have developed alloantibodies against VWF. This study extend our previous finding that mutations responsible for type 3 VWD are scattered throughout the entire VWF gene and that there is no founder effect in these three populations studied.     

Polymorphisms in von Willebrand factor gene promoter influence the glucocorticoid-induced increase in von Willebrand factor: the lesson learned from Cushing syndrome

Cushing syndrome (CS) features high-glucocorticoid secretion and an associated hypercoagulable state often involving an increase in von Willebrand factor (VWF). To identify any influence of VWF promoter on glucocorticoid haemostatic effects, four polymorphic positions (-3267, -2708, -2659 and -2525) segregating as haplotypes 1 (GCAG) or 2 (CTGA) were analysed in 50 CS patients with high VWF (group I) and normal VWF (group II) levels, divided by ABO group. Genotype distribution differed significantly between the two groups: in group I, 25·8% had genotype 1/1, 22·6% had 2/2 and 38·7% had 1/2; in group II, 0% had genotype 1/1, 57·9% had 2/2 and 31·6% had 1/2 ( P  = 0·03). Patients' genotypes also differed from those of controls ( P  = 0·003 for group I, P  = 0·03 for group II). Haplotype 1 was prevalent in group I, haplotype 2 in group II ( P  = 0·002), both with frequencies differing from controls ( P  < 0·001 and P  = 0·009). By odds ratio analysis, genotype 1/1 carried a 12 times greater risk of high-VWF levels than genotype 2/2, and haplotype 1 carried a five times greater risk than haplotype 2. Our findings suggest that VWF promoter haplotypes influence the corticosteroid-mediated increase in VWF.     

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.     

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.     

Haemostatic treatment in connection with surgery in patients with von Willebrand disease

Haemostatic treatment in patients with von Willebrand disease (vWD) in connection with surgery aims at normalizing the haemostatic defect in order to avoid bleeding complications. Factor VIII (FVIII) levels in plasma must be normalized in connection with major surgery, whereas the bleeding time is more important for mucous membrane bleedings. Most patients respond well to treatment with desmopressin which stimulates the endogenous release of FVIII and von Willebrand factor (vWF) and shortens the bleeding time. Non-responders to desmopressin are substituted with a plasma-derived factor concentrate which contains vWF and FVIII. This paper includes a summary of retrospective data from the last 10 years on haemostatic treatment in connection with surgery from four haemophilia centres in Sweden and Denmark on 40 invasive procedures in 27 vWD patients and on one normal delivery. If a FVIII-containing concentrate is given prior to surgery a dose of 30–40 IU VIII:C kg⁻¹ will normalize FVIII levels in most severe cases. If a pure vWF concentrate is used, a dose of 40–50 IU RCoF kg⁻¹ will normalize RCoF in most cases, but FVIII levels will not be normalized until after about 12 h or later. Repeated doses of FVIII-vWF concentrate may lead to very high levels of FVIII in plasma because of the combined effect of the exogenous FVIII-substitution and the endogenous FVIII-release induces by the infused vWF. Dosage should be adjusted according to FVIII levels in plasma.