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Fig. 17.4 Inheritance of vWD

(a) A family pedigree with autosomal dominant segregation, as found in vWD types 1, 2A, 2B and 2M. (Continued.)

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The molecular basis of von Willebrand disease 203

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(b) A family pedigree with autosomal recessive segregation, as found in vWD types 2N and 3.

most of the molecular defects are responsible for null alleles (nonsense, splice site mutations, large gene deletions, small deletions and insertions).

Genetic defects in von Willebrand disease

Type 1 vWD

This is the most common form, accounting for approximately 70% of all cases of vWD. Sometimes type 1 vWD simply represents heterozygosity for a type 3 vWD allele. However, vWF levels in type 1 vWD patients are often considerably reduced below the expected 50% of normal. Individuals with type 1 vWD have very mild to moderate symptoms, a normal or variably prolonged bleeding time, decreased levels of vWF in plasma, and a multimeric structure of vWF. Type 1 vWD may be difficult to diagnose due to natural variations in circulating vWF levels related to the influence of environmental factors, such as exercise, thyroid hormone, estrogens and ABO blood type. vWF levels are lower by up to 30% in individuals with blood group O compared with individuals with other blood groups. Analysis of large kindreds previously classified as having type 1 vWD has shown the presence of phenotypic subtypes of type 1 vWD based upon the behavior of intraplatelet levels of vWF: platelet-normal, platelet-low and platelet-discordant. The mechanism of platelet-low vWD is thought to be defective production of vWF. Another mechanism, associated with platelet-normal vWD, is defective post-translational modification and release of vWF. Platelet-discordant vWD, characterized by normal platelet levels of vWF antigen but low vWF activity, might be due to the latter mechanism or to enhanced clearance of the abnormal vWF.

Although type 1 is the most frequent form of vWD, few mutations have been identified; these are similar to those identified in type 3 vWD (deletions and nonsense and frame-shift mutations). Several patients, clinically presenting as type 1, are compound heterozygotes for a null allele and a type 2N allele. Only two mutations have been shown to cause a clearly dominant type 1 vWD, with high penetrance and very low vWF levels. An in vitro study has clarified the molecular mechanism of the dominant negative missense mutations (C1149R and C1130F) found in the D3 domain. In a random dimerization process occurring in the endoplasmic reticulum, mutant and wild-type pro-vWF subunits form both homodi-mers and heterodimers. Retention of all mutant subunits in the endoplasmic reticulum will reduce the transport of wildtype subunits to the Golgi apparatus by about 50%, whereas subunits arriving in the Golgi apparatus assemble into large multimers and are normally secreted. However, dominant negative mutations appear to be unusual in type 1 vWD and do not always explain the incomplete penetrance and the high frequency of this disorder.

Type 2 vWD

Type 2 vWD is caused by qualitative abnormalities of vWF and accounts for approximately 20% of all vWD cases. Type 2 vWD is caused by a variety of mechanisms, and is associated with a variety of specific defects. This reflects the multifunctional role of vWF and the complicated post-translational processing of this moiety.

Type 2A

This is characterized by decreased platelet-dependent function due to the reduction or absence of high and intermediate molecular weight multimers (Figure 17.5). The bleeding diathesis is caused by the lack of the biologically active high molecular weight multimers. At least two mechanisms are known to produce type 2A vWD, subclassified as group 1 and group 2. Group 1 mutations lead to a vWF subunit that is presumably improperly folded, retained in the endoplasmic reticulum by the cell quality control machinery, and subsequently degraded. Multimers formed by the interactions between normal and mutant subunits are retained in the cell. The largest multimers, as a result of a greater likelihood of mutant subunit content, are more efficiently retained, accounting for the characteristic type 2A multimer pattern and autosomal dominant inheritance. The defect of group 2 does not interfere with biosynthesis and secretion, but instead renders the mutant subunit more susceptible to proteolytic cleavage in plasma by the metalloproteinase ADAMTS-13, which

Fig. 17.5 Comparison of the multimeric structure of plasma vWF from vWD patients and normal subjects

Multimer analysis is performed with a low-resolution discontinuous buffer in a sodium dodecyl sulfate gel electrophoretic system with 1% agarose. Lanes 3 (vWD type 2A) and 4 (vWD type 2B) show the lack of high molecular weight multimers. Lane 2 (vWD type 2M) shows a normal multimeric pattern. Lanes 1 and 5 show a full multimeric structure from a normal control.

Fig. 17.5 Comparison of the multimeric structure of plasma vWF from vWD patients and normal subjects

Multimer analysis is performed with a low-resolution discontinuous buffer in a sodium dodecyl sulfate gel electrophoretic system with 1% agarose. Lanes 3 (vWD type 2A) and 4 (vWD type 2B) show the lack of high molecular weight multimers. Lane 2 (vWD type 2M) shows a normal multimeric pattern. Lanes 1 and 5 show a full multimeric structure from a normal control.

performs a similar function on wild-type vWF, although less efficiently. This enhanced plasma proteolysis results in the selective loss of the larger vWF multimers, very like what is seen in group 1. At least 24 mutations have been reported; they are responsible for both groups, and 20 of these are in the A2 vWF structural domain, the most frequent being R1597W and I1628T.

Type 2B

This uncommon subtype accounts for approximately 5% of all vWD cases. The 2B variant vWF shows increased affinity for platelet glycoprotein Ib and is usually associated with the absence of high molecular weight multimers in circulating plasma but not in platelets (Figure 17.5). The enhanced reactivity of the 2B vWF variant with its platelet receptor results in spontaneous binding to platelets and in thrombocytopenia which is thought to be secondary to the clearance of plate-let-vWF complexes. Type 2B is inherited as a dominant trait. Mutations responsible for this subtype are nearly all contained in the A1 domain, which binds to the Gplb receptor. With a few exceptions, all mutations result in amino acid substitutions, and a few of them (R1306W, R1308C, V1316M and R1341Q) account for 80-90% of the reported cases. Type 2B vWD has sometimes been misdiagnosed and treated as autoimmune thrombocytopenia. Thrombocytopenia and the absence of the larger multimers are not constantly present in type 2B vWD. A few variants have increased GpIb binding with no apparent loss of large multimers and thrombocytopenia, leading to earlier classification among type 1 variants (type 1 New York or type 1 Malmo). With the advent of molecular analysis, these mutations are now correctly classified as type 2B variants.

Type 2M

Type 2M vWD refers to qualitative variants with decreased platelet dependent function not caused by the absence of larger vWF multimers (Figure 17.5). With a pattern of vWF laboratory measurements similar to that of type 2A, type 2M shows a normal multimer distribution (hence M for multimer) or may even show the presence of ultralarge multimers (2M Vicenza). Type 2M is inherited as a dominant trait. The molecular defects are identified in the A1 domain, but in a region different from that of the 2B mutations. These defects, which in most cases are missense mutations, seem to downregulate the binding of the A1 domain to its platelet receptor. An important exception is the 2M Vicenza variant, the candidate mutation being in the D3 domain (R1205H). Furthermore, a second candidate mutation (M740I) has been identified recently in exon 17 in a few patients from the Vi-cenza area.

Type 2N

Type 2N vWD refers to all the qualitative variants characterized by decreased affinity for FVIII. The first description of this type of variant was that of a patient from Normandy (hence the N). This subtype is characterized by low levels of FVIII; however, vWF levels are usually normal and have an intact vWF multimeric pattern. It is difficult to distinguish type 2N from mild hemophilia A. Hemophilia is an X-linked disease, whereas type 2N vWD is an autosomal recessive disease. A definite diagnosis can be made by demonstrating the reduced binding of FVIII to native vWF with assays exploring this vWF property. Since the majority of mutations are located in the N-terminus of the mature vWF subunit (D'-D3), diagnosis can be confirmed by screening for mutations in exons 18, 19 and 20. Three mutations (T791M, R816W and R854Q) account for 90% of the type 2N mutations.

Type 3

Type 3 vWD is an autosomal recessive, clinically severe disorder characterized by the virtual absence of vWF. As in type 2N vWD, there is a secondary deficiency of FVIII and the patients therefore present a double defect of primary hemostasis and intrinsic coagulation. Type 3 vWD is rare and accounts for between 1 and 2% of all vWD cases, with a prevalence in the general population of 0.5-1 per million. The parents of type 3 patients are obligatory heterozygotes and in most cases are asymptomatic, but a minority of them have mild bleeding symptoms. Due to the large size of the gene, the presence of the pseudogene, the low prevalence of the disease and the absence of a specific localization of the mutations, the characterization of the molecular defects in type 3 has been relatively slow. Southern blot analysis first allowed the identification of large gene deletions, found in the majority of the patients who had developed alloantibodies to vWF after transfusion. However, the use of more specific and sensitive screening methods, such as single-strand conformational polymorphism, chemical cleavage mismatch analysis, and conformational sensitive gel electrophoresis, allowed the identification of most of the mutations in these patients. The most common mutations in type 3 vWD are nonsense mutations, small deletions, small insertions and splice-site mutations. Among the nonsense mutations, a few hotspot mutations at the arginine codons (R365X, R1659X, R1853X and R2535X) have been found repeatedly in different populations. A single cytosine deletion in a stretch of six cytosines in exon 18 appears to be particularly common in patients from Sweden and Germany. Although most of the mutations determine null alleles, a few in-frame deletions and several missense mutations have been identified. Patients with type 3 vWD may develop alloantibodies to vWF, which render replacement therapy ineffective. This complication is strongly associated with the presence of large gene deletions, although a few cases have been reported due to nonsense mutation.

Treatment of von Willebrand disease

While the treatment of patients with hemophilia A and B is facilitated by the close relationships existing between the content of FVIII or factor IX in the replacement material, the plasma levels attained after infusion and clinical efficacy, this model cannot be easily translated into the evaluation of products for the treatment of vWD, because it is still unclear which FVIII or vWF measurement in therapeutic products or in patient plasma correlates best with the severity of clinical bleeding and the efficacy of treatment. The situation is further complicated by the fact that vWD subtypes respond differently to treatment. Two main therapeutic agents are currently used to stop spontaneous bleeding and to prevent bleeding at the time of surgical procedures: the non-transfusional agent desmopressin and blood products that contain FVIII and vWF concentrated from plasma. Ancillary forms of treatment are platelet concentrates, synthetic fibrinolysis inhibitors and oral estrogen-progestogen preparations, which, in some clinical situations, are adjunctive or sometimes alternative to the two main treatments.

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analog of the antidiuretic hormone vasopressin that, when administered to healthy volunteers or patients with mild hemophilia and vWD, increases FVIII and vWF transiently by releasing these moieties from storage sites into the plasma. Endothelial cell Weibel-Palade bodies appear to be the source of vWF, but the source of FVIII has not yet been determined. Desmopressin induces vWF release into plasma by binding to the vasopressin V2 receptor and thereby activating cyclic AMP-mediated signaling in vascular endothelial cells.

The advantage of this compound is that it is relatively inexpensive and carries no risk of transmitting blood-borne infectious agents. When infused intravenously over 30 minutes at a dose of 0.3 |lg/kg, desmopressin is expected to increase plasma FVIII and vWF three- to five-fold above the basal levels. In general, high FVIII/vWF concentrations last for at least 8-10 hours in plasma. Patients with baseline plasma levels of FVIII/vWF measurements in the range of 10-20 IU/dl or more are those who are more likely to reach desmopres-sin levels sufficient to attain hemostasis after desmopressin treatment, taking into account variables such as the type and severity of the bleeding episode and the levels of FVIII/vWF that must be attained and maintained to secure hemostasis. Even though most patients with mild hemophilia A that is treated repeatedly with desmopressin become less responsive to therapy, this problem is less frequent and prominent in patients with type 1 vWD. The drug is also available in concentrated forms for subcutaneous and intranasal administration (at doses of 0.3 |ig/kg and 150-300 |g, respectively), which can be convenient for home treatment.

Side effects of desmopressin are usually mild tachycardia, headache and flushing. Hyponatremia and volume overload due to the antidiuretic effect of desmopressin are relatively rare if fluid intake is not excessive during treatment. Even though no thrombotic episodes have been reported in vWD patients treated with desmopressin, this compound should be used with caution in elderly patients with cardiovascular disease, because a few cases of myocardial infarction and stroke have occurred in treated patients with hemophilia and uremia. Desmopressin has little or no oxytocic activity and has been used by us without mishap during the early period of pregnancy in 31 women with low FVIII levels (including carriers of hemophilia A and vWD patients) to prevent bleeding at the time of invasive diagnostic procedures such as chori-onic villus sampling and amniocentesis.

Desmopressin is most effective in patients with type 1 vWD, particularly in those who have releasable vWF in storage sites, a condition usually reflected by normal vWF levels in platelets. In these patients FVIII, vWF and the bleeding time are usually corrected to normal values by desmopressin. In other vWD subtypes, responsiveness is varied (Table 17.2).

Table 17.2 Indications for desmopressin in different types of von

Willebrand disease.

Type of disease

Response

1

Usually effective

2A

Usually ineffective

2B

May be contraindicated

2M

Predicted to be ineffective

2N

Partially effective

3

Ineffective

A poor and short-lasting response is seen in patients with the variant of type 1 vWD characterized by low levels of platelet vWF, perhaps because low levels in platelets are paralleled by low levels of releasable vWF in storage sites. In type 2A, FVIII levels are usually increased by desmopressin but the bleeding time is shortened in only a minority of cases. Desmopressin is contraindicated in type 2B, because of the transient appearance of thrombocytopenia. There is little experience in type 2M, but a poor response is predicted because vWF is dysfunctional in this subtype. In type 2N, levels of FVIII clotting activity increase after desmopressin, but released FVIII circulates for a relatively short time period in patients' plasma because the stabilizing effect of the abnormal vWF on FVIII is impaired. Therefore, plasma concentrates containing FVIII and vWF are preferable. Patients with type 3 vWD are usually unresponsive to desmopressin, because they lack releasable stores of vWF.

Transfusional therapy with plasma products containing both FVIII and vWF is the treatment of choice when bleeding occurs or must be prevented and the predicted response to desmopressin is considered suboptimal for hemostasis. FVIII and vWF may be infused as fresh frozen plasma (FFP) but the large volumes required limit its use. Cryoprecipitate contains five to ten times more FVIII and vWF than FFP (each bag contains approximately 80-100 IU). Early studies indicated that cryoprecipitate administered every 12-24 hours normalized plasma FVIII levels and stopped or prevented bleeding in vWD. On the basis of these observations, cryoprecipitate has been the mainstay of treatment for many years. However, virucidal methods cannot be applied to cryoprecipitate as currently produced by blood banks, so that this product carries a small but definite risk of transmitting blood-borne infectious agents. Therefore, virus-inactivated FVIII/vWF concentrates, originally developed for the treatment of hemophilia A, are currently perceived as safer and are preferred in the management of vWD patients unresponsive to desmopressin.

Two commercially available concentrates have been evaluated more extensively than others and clinical studies have demonstrated their efficacy in preventing or stopping bleed ing. One, licensed in the USA and in several European countries for the treatment of vWD, contains a relatively larger amount of vWF (measured as vWF:RCo) than of FVIII (approximately two to three times more in terms of IU). The virucidal method adopted is pasteurization. The other, licensed only in Europe so far, differs because it contains similar relative amounts of FVIII and vWF:RCo. Two virucidal methods, solvent/detergent and heating at high temperatures, are included in the manufacturing step, with the goal of inactivating both enveloped and non-enveloped virus. Other virally inactivated FVIII/vWF concentrates have been successfully employed in vWD patients, but clinical experience is more limited. Recently, a chromatography-purified concentrate that is particularly rich in vWF but has a low FVIII content has also been produced and evaluated. This concentrate was clinically efficacious when tested in a small number of type 3 vWD patients. Efficacy and safety are now under evaluation in Europe in larger series of patients.

The dosages recommended for the control or prevention of bleeding are summarized in Table 17.3. Dosages are expressed in IU/kg of FVIII because most of the available concentrates, being manufactured for the treatment of patients with hemophilia A, are labeled in terms of FVIII content only. Since FVIII has a longer half-life in vWD patients than in patients with hemophilia A (20-24 versus 12-14 hours), the infusion of one daily dose is sufficient to reach and maintain adequate plasma levels for the treatment of spontaneous bleeding episodes and to prevent excessive bleeding until healing is complete, depending on the site and extent of surgery. Since in the USA the Food and Drug Administration requires that plasma products licensed for treatment of vWD patients are labeled in terms of the actual defective protein to be replaced, the solvent/detergent, heat-treated concentrate is labeled in terms of vWF: RCo content. The doses of this concentrate recommended for their demonstrated efficacy in a large, prospective clinical trial are 40-60 IU/kg of vWF:RCo (50-75 IU/kg in children because of the lower in vivo recovery), which usually results in plasma levels of vWF:RCo of 80-120 IU/dl or higher. Since the plasma half-life of vWF:RCo is much shorter than that of FVIII:C (6-8 versus 20-24 hours), usually these doses should not be repeated more often than every 24 hours in order to avoid very high levels of FVIII:C, which may engender venous thromboembolic complications.

It is usually not necessary to carry out laboratory tests to monitor replacement therapy in patients with spontaneous bleeding episodes. For surgical procedures we recommend measuring FVIII every 12 hours on the operation day and then every 24 hours. The FVIII response can be predicted on the basis of pharmacokinetic data which indicate that 1 IU/ kg will increase plasma FVIII levels by approximately 2 IU/dl (1.5 IU/dl in children). Those who use concentrates labeled in terms of vWF:RCo content may choose to monitor the plasma level of this moiety, although this is more complex to measure in the clinical setting and less standardized than the FVIII level. It remains to be demonstrated whether newer laboratory measurements, such as the collagen binding assay, will be simpler and more predictive of outcome.

Monitoring the bleeding time is usually not necessary. The prolonged bleeding time is frequently not normalized or even shortened in patients treated with FVIII/vWF concentrates. There are probably multiple reasons for the inconsistent effects of plasma products on the bleeding time. So far, no concentrate contains a fully functional vWF, as tested in vitro by evaluating the multimeric pattern and using functional assays. Despite no or partial correction of the bleeding time, major surgical procedures are successfully carried out and spontaneous bleeding episodes controlled following the infusion of FVIII/vWF concentrates. In the relatively rare instances when bleeding is not controlled and the bleeding time remains prolonged, platelet concentrates (given immediately after FVIII/vWF-containing preparations, at doses of 4 to 5 X 1011 platelets) are effective, particularly in patients with type 3 vWD, both in terms of bleeding time correction and the control of hemorrhages. Platelets from type 3 vWD patients

Table 17.3 Dosages of FVIII coagulant activity (FVIII:C) recommended in patients with von Willebrand disease treated with FVIII/vWF

concentrates.*

Type of bleeding

Dose (IU/kg)

Number of infusions

Target

Major surgery

40-60

Once a day

Maintain plasma FVIII:C >50 IU/dl until healing is

complete depending on the type of surgery

Minor surgery

30-50

Once a day or every other day

FVIII:C >30 IU/dl until healing is complete de

pending on the type of surgery

Dental extractions

20-30

Single

FVIII:C >30 IU/dl for at least 12 hours

Spontaneous bleeding episodes

20-30

Single

FVIII:C >30 IU/dl

*For concentrates labeled in terms of vWF:RCo, the recommended doses for adults, the number of infusions and the target plasma levels are

the same as those for FVIII:C.

Table 17.4 Summary of management of different types and subtypes of von Willebrand disease.

Treatment of choice

Alternative or adjunctive therapy

Type 1 Type 2A Type 2B Type 2M Type 2N Type 3

Type 3 complicated by alloantibodies

Desmopressin

Factor VIII/vWF concentrates Factor VIII/vWF concentrates Factor VIII/vWF concentrates Factor VIII/vWF concentrates Factor VIII/vWF concentrates Recombinant factor VIII

Antifibrinolytic amino acids

Antifibrinolytic amino acids

Antifibrinolytic amino acids

Antifibrinolytic amino acids

Antifibrinolytic amino acids

Antifibrinolytic amino acids, platelet concentrates

Recombinant activated factor VII

lack vWF completely and there is no uptake of the protein from plasma after infusion of concentrates. The hemostatic effectiveness of the transfusion of normal platelets is likely to be due to the fact that these cells transport and localize vWF at sites of vascular injury. From a practical standpoint, it must be emphasized that in the largest prospective study carried out so far in vWD patients platelet concentrates became necessary to prevent or stop bleeding in one case only.

The different options available at the moment for the management of von Willebrand disease are summarized in Table 17.4. Treatment of spontaneous bleeding episodes and their prevention at the time of an invasive procedure is relatively simple and can certainly be tackled by the average clinical he-matologist with access to a minimum of laboratory testing (FVIII assays). However, the patients need to be well characterized phenotypically because the choice of treatment must be tailored to the different types and subtypes of the disease. Such characterization is not simple, so that at most clinical centers it is probably not worthwhile setting up relatively complicated tests, such as multimer analysis and the vWF: RCo assay, when samples can be sent for analysis to more expert laboratories that have become proficient during the study of large series of patients.

Von Willebrand disease resources on the Internet

ISTH SSC vWF: www.shef.ac.uk/vwf/index.html

The Human Gene Mutation Database, Cardiff: archive.uwcm.

ac.uk/uwcm/mg/search/119125.html OMIMTM On line Mendelian Inheritance in Man: www.ncbi.

nlm.nih.gov/entrez/dispomim.cgi?id=193400 GeneCards™ is a database of human genes: bioinfo.weizmann. ac.il/cards-bin/carddisp?vWF

Further reading General

Michiels JJ (ed.) (2001) Von Willebrand factor and von Willebrand disease. Best Practice & Research. Clinical Haematology, 14, 235-462.

Sadler JE, Mannucci PM, Berntorp E etal. (2000) Impact, diagnosis and treatment of von Willebrand Disease. Thrombostasis and Haemosta-sis, 84, 160-174.

Von Willebrand factor

Mancuso DJ, Tuley EA, Westfield LA et al. (1989) Structure of the gene for human von Willebrand factor. Journal of Biological Chemistry, 264, 19514-19527.

Mancuso DJ, Tuley EA, Westfield LA et al. (1991) Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry, 30, 253-269.

Shelton-Inloes BB, Titani K, Sadler JE. (1986) cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry, 25, 3164-3171.

Wagner DD, Marder VJ. (1984) Biosynthesis of von Willebrand protein by human endothelial cells: processing steps and their intracellular localization. Journal of Cell Biology, 99, 2123-2130.

Von Willebrand disease and its classification

Nichols WC, Ginsburg D. (1997) von Willebrand disease. Medicine (Baltimore), 76, 1-20.

Sadler JE. (1994) A revised classification of von Willebrand disease. Thrombosis and Haemostasis, 71, 520-525.

Genetic defects in von Willebrand disease

Dent JA, Berkowitz SD, Ware J et al. (1990) Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proceedings of the National Academy of Sciences of the United States of America, 87, 6306-6310.

Eikenboom JCJ, Matsushita T, Reitsma PH et al. (1996) Dominant type I von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood, 88, 2433-2441.

Keeney S, Cumming AM. (2001) The molecular biology of von Willebrand disease. Clinical and Laboratory Haematology, 23, 209-230.

Lyons SE, Bruck ME, Bowie EJW et al. (1992) Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. Journal of Biological Chemistry, 267, 4424-4430.

Mazurier C, Dieval J, Jorieux S et al. (1990) A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction. Blood, 75, 20-26.

Saba HI, Saba SR, Dent JA et al. (1985) Type IIB Tampa: a variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation. Blood, 66, 282-286.

Schneppenheim R, Federici AB, Budde U et al. (2000) von Willebrand disease type 2M 'Vicenza' in Italian and German patients: identification of the first candidate mutation (G3864A; R1205H) in 8 families.

Thrombostasis and Haemostasis, 83, 136-140.

Shelton-Inloes BB, Chehab FF, Mannucci PM et al. (1987) Gene deletions correlate with the development of alloantibodies in von Willebrand disease. Journal of Clinical Investigation, 79, 1459-1465.

Zhang ZP, Blombäck M, Egberg N et al. (1994) Characterization of the von Willebrand factor gene (vWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin. Genomics, 21, 188-193.

Treatment of von Willebrand disease

Castillo R, Escolar G, Monteagudo J et al. (1987) Hemostasis in patients with severe von Willebrand disease improves after normal platelet transfusion and normalizes with further correction of the plasma defect. Transfusion, 37, 785-790.

Castillo R, Monteagudo J, Escolar G et al. (1991) Hemostatic effect of normal platelet transfusion in severe von Willebrand disease patients. Blood, 77, 1901-1905.

Chang AC, Rick ME, Ross PL et al. (1998) Summary of a workshop on potency and dosage of von Willebrand factor concentrates. Haemophilia, 4 Supplement 3, 1-6.

Dobrkovska A, Krzensk U, Chediak JR. (1998) Pharmacokinetics, efficacy and safety of Humate-P in von Willebrand disease. Haemophilia, 4 Supplement 3, 33-39.

Goudemand J, Negrier C, Ounnoughene N et al. (1998) Clinical management of patients with von Willebrand's disease with a VHP vWF concentrate: the French experience. Haemophilia, 4 Supplement 3, 48-52.

Kaufmann JE, Oksche A, Wollheim CB et al. (2000) Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. Journal of Clinical Investigation, 106, 107-116.

Mannucci PM. (1997) Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood, 90, 2515-2521.

Mannucci PM, Federici AB. (1995) Antibodies to von Willebrand factor in von Willebrand disease. In: Aledort LM, Hoyer LW, Reisner HM et al. (eds). Inhibitors to Coagulation Factors, Volume 386. New York: Plenum Press, pp. 87-92.

Mannucci PM, Ruggeri ZM, Pareti FI et al. (1977) 1-Deamino-8-D-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrand disease. Lancet, i, 869-872.

Mannucci PM, Bettega D, Cattaneo M. (1992) Consistency of responses to repeated DDAVP infusions in patients with severe vWD and alloantibodies to vWF. European Journal of Haematology, 82, 87-93.

Mannucci PM, Tenconi PM, Castaman G et al. (1992) Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial. Blood, 79, 3130-3137.

Mannucci PM, Chediak J, Hanna W et al. and the Alphanate Study Group. (2002) Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective multicenter study. Blood, 99, 450-456.

Mazurier C, Gaucher C, Jorieux S etal. (1994) Biological effect of desmopressin in eight patients with type 2N ('Normandy^ von Willebrand disease. British Journal of Haematology, 88, 849-854.

Rodeghiero F, Castaman G, Meyer D et al. (1992) Replacement therapy with virus-inactivated plasma concentrates in von Willebrand disease. Vox Sanguinis, 62, 193-199.

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