Molecular Genetics of Type 2 von Willebrand Disease

Type 2 von Willebrand disease (VWD) is characterized by a wide heterogeneity of functional and structural defects. These abnormalities' cause either defective von Willebrand factor (VWF)-dependent platelet function in subtypes 2A, 2B, and 2M or defective VWF-factor VIII (FVIII) binding in subtype 2N. The diagnoses of types 2A, 2B, and 2M VWD may be guided by the observation of disproportionately low levels of ristocetin cofactor activity or collagen-binding capacity relative to VWF antigen. The abnormal platelet-dependent function is often associated with the absence of high molecular weight (HMW) multimers (type 2A, type 2B), but the HMW multimers may also be present (type 2M, some type 2B), and supranormal multimers may exist ("Vicenza" variant). The observation of a low FVIII-to-VWF:Ag ratio is a hallmark of type 2N VWD. in which the FVIII levels depend on the severity of the FVIII-binding defect. Today, the identification of mutations in particular domains of the pre-pro-VWF is helpful in classifying these variants and providing further insight into the structure-function relationship and the biosynthesis of VWF. Thus, mutations in the D2 domain, involved in the multimerization process, are found in patients with type 2A, formerly named IIC VWD. Mutations located in the D' domain or in the N terminus of the D3 domain define type 2N VWD. Mutations in the D3 domain characterize Vicenza and IIE patients. Mutations in the A1 domain may modify the binding of VWF multimers to platelets, either increasing (type 2B) or decreasing (type 2M, 2A/2M) the affinity of VWF for platelets. In type 2A VWD, molecular abnormalities identified in the A2 domain, which contains a specific proteolytic site, are associated with alterations in folding, impairing VWF secretion or increasing its susceptibility to proteolysis. Finally, a mutation localized in the carboxy-terminus CK domain, which is crucial for the dimerization of the VWF subunit, has been identified in a rare subtype 2A, formerly named IID.     

Characterization of recessive severe type 1 and 3 von Willebrand Disease (VWD), asymptomatic heterozygous carriers versus bloodgroup O-related von Willebrand factor deficiency, and dominant type 1 VWD.

Recessive type 3 von Willebrand disease (VWD) is caused by homozygosity or double heterozygosity for two non-sense mutations (null alleles). Type 3 VWD is easy to diagnose by the combination of a strongly prolonged bleeding time (BT), absence of ristocetine-induced platelet aggregation (RIPA), absence of von Willebrand factor (VWF) protein, and prolonged activated partial thromboplastin time (aPTT) due to factor VIII:coagulant (FVIII:C) deficiency. VWD type 3 is associated with a pronounced tendency to mucocutaneous and musculoskeletal bleedings since early childhood. Carriers of one null allele are usually asymptomatic at VWF levels of 50% of normal. Recessive severe type 1 VWD is caused by homozygosity or double heterozygosity for a missense mutation. Recessive type 1 VWD differs from type 3 VWD by the presence of detectable von Willebrand factor: antigen VWF:Ag and FVIII:C levels between 0.09 and 0.40 U/mL. Patients with recessive type 1 VWD show an abnormal VWF multimeric pattern in plasma and/or platelets consistent with severe type 2 VWD. Carriers of a missense mutation may have mild bleeding and mild VWF deficiency and can be diagnosed by a double VWF peak on cross immunoelectrophoresis (CIE). There will be cases of mild and moderate recessive type 1 VWD due to double heterozygosity of two missense mutations, or with the combination of one missense mutation with a non-sense or bloodgroup O. Mild deficiency of VWF in the range of 0.20 to 0.60 U/mL, with normal ratios of von Willebrand factor: ristocetine cofactor/antigen VWF:RCo/Ag and VWF:collagen binding/antigen (VWF:CB/Ag), normal VWF multimers, and a completely normal response to desmopressin acetate (DDAVP) with VWF level rising from below to above 1.00 U/mL are very likely cases of so-called pseudo-VWF deficiency in individuals with normal VWF protein and gene. Autosomal dominant type 1 VWD variants are in fact type 2 variants caused by a heterozygous missense mutation in the VWF gene that produces a mutant VWF protein that has a dominant effect on normal VWF protein produced by the normal VWF allele with regard to the synthesis, processing, storage, secretion, and/or proteolysis of VWF in endothelial cells. A DDAVP challenge test clearly differentiates between dominant type 1 VWD phenotype and dominant type 2 M VWD.     

Intravenous DDAVP and factor VIII-von Willebrand factor concentrate for the treatment and prophylaxis of bleedings in patients With von Willebrand disease type 1, 2 and 3.

The current standard set of von Willebrand factor (VWF) parameters used to differentiate type 1 from type 2 VWD include bleeding times (BTs), factor VIII coagulant activity (FVIII:C), VWF antigen (VWF:Ag), VWF ristocetine cofactor activity (VWF:RCo), VWF collagen binding activity (VWF:CB), ristocetine induced platelet aggregation (RIPA), and analysis of VWF multimers in low and high resolution agarose gels and the response to DDAVP. The BTs and RIPA are normal in asymptomatic carriers of a mutant VWF allele, in dominant type 1, and in recessive type 2N VWD, and this category has a normal response of VWF parameters to DDAVP. The response of FVIII:C is compromised in type 2N VWD. The BTs and RIPA are usually normal in type Vicenza and mild type 2A VWD, and these two VWD variants show a transiently good response of BT and VWF parameters followed by short in vivo half life times of VWF parameters. The BTS are strongly prolonged and RIPA typically absent in recessive severe type 1 and 3 VWD, in dominant type 2A and in recessive type 2C (very likely also 2D) VWD and consequently associated with low or absent platelet VWF, and no or poor response of VWF parameters to DDAVP. The BTs are prolonged and RIPA increased in dominant type 2B VWD, that is featured by normal platelet VWF and a poor response of BT and functional VWF to DDAVP. The BTs are prolonged and RIPA decreased in dominant type 2A and 2U, that all have low VWF platelet, very low VWF:RCo values as compared to VWF:Ag, and a poor response of functional VWF to DDAVP. VWD type 2M is featured by the presence of all VWF multimers in a low resolution agarose gel, normal or slightly prolonged BT, decreased RIPA, a poor response of VWF:RCo and a good response of FVIII and VWF:CB to DDAVP and therefore clearly in between dominant type 1 and 2U. The existing recommendations for prophylaxis and treatment of bleedings in type 2 VWD patients with FVIII/VWF concentrates are mainly derived from pharmocokinetic studies in type 3 VWD patients. FVIII/VWF concentrates should be characterised by labelling with FVIII:C, VWF:RCo, VWF:CB and VWF multimeric pattern to determine their safety and efficacy in prospective management studies. As the bleeding tendency is moderate in type 2 and severe in type 3 VWD and the FVIII:C levels are near normal in type 2 and very low in type 3 VWD patients. Proper recommendations of FVIII/VWF concentrates using VWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are proposed and has to be stratified for the severity of bleeding, the type of surgery either minor or major and for type 2 and type 3 VWD as well.     

von Willebrand disease "Vicenza" with larger-than-normal (supranormal) von Willebrand factor multimers

When normal volunteers or patients with type I von Willebrand disease (VWD) are given desmopressin (DDAVP), a set of larger-than-normal (supranormal) von Willebrand factor (VWF) multimers, similar to those present in VWF-containing cells such as platelets megakaryocytes and endothelial cells, appear transiently in postinfusion plasma. In two kindreds with mild lifelong bleeding symptoms transmitted as an autosomal dominant trait, all ten symptomatic members (but none of the five asymptomatic members) had a supranormal multimeric structure for plasma VWF, apparently identical to that seen for postdesmopressin normal plasma. Plasma factor VIII coagulant activity (VIII:C), VWF antigen (VWF:Ag), ristocetin-induced platelet agglutination, and ristocetin cofactor (RiCof) activity were low. Platelet VWF:Ag and RiCof levels (tested for three patients only) were normal. Bleeding times were normal or slightly prolonged. The patients' platelet multimeric structure was the same as that for normal platelets. After desmopressin infusion the plasma VWF multimeric structure remained supranormal as for preinfusion plasma, with VIII:C VWF:Ag and RiCof increasing markedly over baseline values and disappearing at a normal rate. Examination of the VWF subunit composition from three of these patients indicated that proteolytic processing of their VWF did not differ from normal. This study describes the first variant of VWD with a supranormal multimeric structure.     

Autosomal dominant C1149R von Willebrand disease: phenotypic findings and their implications

Background

Mutation C1149R in the von Willebrand factor (VWF) gene has been thought to cause autosomal dominant severe type 1 von Willebrand disease (VWD).

Design and Methods

Eight patients from three unrelated families with this mutation were included in the present study who had distinct VWF abnormalities, not described in earlier studies.

Results

The patients showed notably low levels of VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding (VWF:CB), and a reduced ristocetin-induced platelet aggregation (RIPA). VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios were lower than 0.7. At basal conditions, all the VWF multimers were decreased in plasma, with a clearly lower relative proportion of the high molecular weight VWF multimers (HMWM). In high-resolution agarose gels, a large decrease in the relative proportions of the satellite bands was seen. The patients had a brief good response to desmopressin (DDAVP) administration, but the released VWF half-life was shorter than normal, indicating an accelerated clearance of their VWF. Platelet VWF was abnormal.

Conclusions

We conclude from the results obtained in these patients for plasma phenotypic data that this mutation should be classified as a VWD type 2A (IIE). DDAVP therapy may be somewhat helpful for this mutation, at least for mild to moderate bleeding. These data provide evidence that for VWD classification factors other than basal VWF, such as DDAVP response and platelet VWF, should be considered.     

Von Willebrand Disease Lab Diagnosis

The hemorrhagic diseases are characterized by bleeding which can vary considerably according to their severity. The von Willebrand disease (VWD) is the most frequent hereditary hemorrhagic disease and the prevalence of clinically significant disease is probably closer to 1:1000, being an extremely heterogeneous and complex disorder that is related to the deficiency in concentration, structure or function of von Willebrand factor (VWF). The VWD is divided into type 1, with partial deficiency of the VWF, type 2, with qualitative defects in the molecule with four subdivisions, and type 3, with very low or undetectable levels of plasma and platelet VWF and ristocetin cofactor activity. The laboratory diagnosis of VWD is complex. Specific tests that assess the functionality and concentrations of the VWF and FVIII are needed. The routine tests are the bleeding time, the activated partial thromboplastin time and the platelet count, however, singly, they may not suggest the diagnosis of VWD, requiring further specific tests, such as VWF function evaluation through its ristocetin cofactor assay (VWF:RCo), VWF protein concentration immunoassay (VWF:Ag), the factor VIII coagulation assay (FVIII:C), VWF binding to immobilized collagen (VWF:CB), ristocetin-induced platelet aggregation (RIPA), VWF multimers patterns, factor VIII binding of immobilized VWF (VWF:FVIIIB), among others. From the moment the diagnosis is confirmed, the appropriate treatment for each patient is sought, with the purpose of increasing plasma concentrations of the deficient protein, both in bleeding episodes, as for invasive procedures. Although diagnosis facilitates treatment other approach in the present scenario is prenatal diagnosis which, is the need of the hour.     

The von Willebrand factor collagen-binding activity assay: clinical application

A collagen type III based collagen-binding assay was developed for measuring the functional activity of the von Willebrand factor. The assay had a low coefficient of variance (4.8%) for normal values under optimized conditions. The results of the collagen-binding activity (CBA) assay correlated with ristocetin cofactor activity tested in normal plasma samples (n=29). We found that the CBA of blood group O is lower than that of other blood groups. The test was used for the diagnosis of von Willebrand's disease (VWD) and for estimating the response to treatment with DDAVP (1-deamino-D-arginine-8 vasopressin) and factor VIII concentrate. A mean ratio of VWF antigen (VWF:Ag) to CBA of 1.5 indicated type 1 and of 2.7 indicated type 2 VWD. The increase in the collagen-binding activity of VWF released in type 1 VWD patients (n=7) after treatment with DDAVP was higher than the increase in the VWF antigen; this is characteristic of very high multimers with greater functional activity. Factor VIII concentrate Koate-HP (Bayer) administered to a patient with VWD type 3 had a mean residence time of 12.6 h for VWF:Ag and 11.2 h for CBA. These findings suggest that the collagen-binding assay is a useful test for measuring the functional activity of VWF in plasma samples, factor VIII concentrates, as well as for estimating the outcome of treatment.     

Mild forms of von Willebrand disease: diagnosis and management

Diagnosis of mild forms of type 1 and 2 von Willebrand disease (VWD) may be difficult, especially when the levels of von Willebrand factor (VWF) activities measured as ristocetin cofactor are close to normal (30-60 U/dL) because the laboratory phenotype is highly heterogeneous and confounded by factors outside the VWF gene (eg, blood group) that may influence VWF levels. An array of tests is often required to characterize the VWD types of the disorder and establish the best treatment modality, but laboratory data should always be interpreted in the presence of personal and family bleeding history. The aim of treatment is to correct the dual defect of hemostasis (ie, abnormal coagulation expressed by low levels of factor VIII:C and abnormal platelet adhesion expressed by the prolonged bleeding time). Desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP) is the treatment of choice for the mild forms of type 1 and 2 VWD because it often corrects the factor VIII/VWF levels and the prolonged bleeding time in most patients, but no prospective studies on clinical effects of DDAVP are available. In type 1 and type 2 VWD unresponsive to DDAVP, plasma virally inactivated concentrates containing VWF and factor VIII are the mainstay of treatment.     

Lack of multimer organization of von Willebrand factor in an acquired von Willebrand syndrome

We report a case of acquired von Willebrand syndrome (AVWS) in a 20-year-old-woman with systemic lupus erythematosus, in whom severe bleeding complications followed kidney biopsy. Coagulation studies demonstrated undetectable levels of ristocetin-induced platelet aggregation (RIPA), von Willebrand factor antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo), associated with significantly prolonged bleeding time; unlike type 3 von Willebrand disease (VWD), platelet VWF was reduced but not undetectable. The plasma VWF multimer pattern was characterized by the presence of only two bands, one of low molecular weight (MW) running as the protomer of plasma VWF in normals, the other of abnormally high MW without detectable intermediate multimers; this pattern resembles that of VWF present in endothelial cells. A search for an anti-VWF antibody demonstrated the presence of an inhibitor at high titre. This anti-VWF antibody did not interfere in the interaction of VWF with platelet glycoprotein (GP) Ib through the A1 domain, and did not react with the A2 domain of VWF; instead, it seemed to modify the relative representation of high and low MW VWF multimers released by normal human umbilical vein endothelial cells (HUVEC). After Azathioprine and corticosteroid treatment, the anti-VWF antibody disappeared and the patient's haemostatic profile normalized, except for the platelet VWF content which still remained decreased. We suggest that the anti-VWF antibody present in the AVWS described compromised both circulating VWF levels and their multimeric organization, inducing the maintenance of the multimer structure that VWF normally has before or in the early phase after secretion from endothelial cells.     

Management of inherited von Willebrand disease in 2006

The aim of treatment of von Willebrand disease (VWD) is to correct the dual defect of hemostasis (i.e., the abnormal platelet adhesion due to reduced and/or dysfunctional von Willebrand factor [VWF] and the abnormal coagulation expressed by low levels of factor [F] VIII). Desmopressin acetate (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. Prospective studies on biological response versus clinical efficacy of DDAVP in VWD types 1 and 2 are in progress to explore its benefits and limits as a therapeutic option. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective, and for these patients plasma virally inactivated concentrates containing VWF and FVIII are the mainstay of treatment. Several intermediate- and high-purity VWF/FVIII concentrates are available and have been shown to be effective in clinical practice (bleeding and surgery). New VWF products almost devoid of FVIII are now under evaluation in clinical practice. Although thrombotic events are rare in VWD patients receiving repeated infusions of concentrates, there is some concern that sustained high FVIII levels may increase risk of postoperative venous thromboembolism. Dosage and timing of VWF/FVIII administrations should be planned to keep the FVIII level between 50 and 150 IU/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long-term prophylaxis for recurrent bleedings.     

The reduction of large von Willebrand factor multimers in plasma in essential thrombocythaemia is related to the platelet count

We have investigated the relationship between platelet count and large VWF (von Willebrand factor) multimers in the plasma of 36 patients with essential thrombocythaemia (ET) and 26 patients with reactive thrombocytosis (RT). In both ET and RT patients an inverse relationship could be established between platelet count and large VWF multimers in plasma as well in relatively decreased ristocetin cofactor/von Willebrand factor antigen and collagen binding activity/von Willebrand factor antigen ratios. A normalization of the platelet count was accompanied by restoration of a normal plasma VWF multimeric distribution. Our data suggest that increasing numbers of platelets circulating in blood result in increased removal of large VWF multimers from plasma.     

Laboratory monitoring of replacement therapy for major surgery in von Willebrand disease

Von Willebrand disease (VWD) is an inherited haemorrhagic disorder caused by a quantitative or qualitative defect of von Willebrand factor (VWF), a multimeric plasma glycoprotein that plays a key role in platelet adhesion to the subendothelium and acts as a carrier of factor VIII (FVIII) in blood. Patients with VWD experience bleeding symptoms that are mainly localized in mucous membranes and soft tissues, and their severity depends on the degree of the primary reduction in VWF and the secondary deficiency of FVIII in plasma. Because VWD patients are also at increased risk of perioperative bleeding, a prophylactic treatment aimed to correct the dual haemostatic defect (i.e. VWF and FVIII) is warranted. This review summarizes knowledge on the current management of patients undergoing major surgery, focusing on the peri‐surgical laboratory monitoring of replacement therapy with VWF/FVIII concentrates. We suggest to monitor plasma levels of FVIII coagulant activity in the postoperative period rather than a surrogate maker of platelet‐binding VWF activity as the ristocetin cofactor assay and its recent modifications.     

Type 2N von Willebrand disease due to Arg91Gln substitution and a cytosine deletion in exon 18 of the von Willebrand factor gene

Two members of a family previously classified as type 1 von Willebrand disease (VWD), showed a quantitative defect in von Willebrand factor (VWF) antigen and ristocetin cofactor activity and an abnormal capacity of VWF to bind FVIII. Sequencing of the VWF gene region coding for the FVIII binding domain revealed the most frequent type 2N mutation: a single nucleotide change (G2811A) in exon 20, resulting in substitution of glutamine (Gln) for arginine (Arg) 91 in the mature VWF protein in one allele. The other allele contained a cytosine deletion (2680delC) in exon 18, introducing a premature stop codon at position 79 (Val79X) which produced a quantitative defect in VWF levels. The Arg91Gln defect is usually not evident in heterozygotes; however, in these patients it was expressed due to the lack of VWF production from the other allele. This is the first report of type 2N VWD in Italy.     

Similarity in joint and mucous bleeding syndromes in type 2N von Willebrand disease and severe hemophilia A coexisting with type 1 von Willebrand disease in two Chinese pedigrees

In this study, we investigated the molecular basis of two unrelated Chinese patients with hemostatic disorders. The proband of the first family had severe hemophilia A (HA) coexisting with type 1 von Willebrand disease (VWD) and the proband of the second family had type 2N VWD. Both probands had similar phenotypes, which included joint and mucosal bleeding, very low factor VIII (FVIII) activity (FVIII:C), and moderate reductions in VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:Rco), as well as a normal multimeric pattern. One FVIII mutation and three VWF mutations were identified: FVIII p.R446* and VWF heterozygous p.E216K mutations were detected in proband 1 and compound heterozygosity of VWF mutations (p.R816W and c.1911delC) in proband 2. Transient expression studies in HEK293T cells proved that R816W mutation abolished the binding of FVIII to VWF and slightly impaired protein synthesis and secretion; 1911delC mutation mainly impaired VWF protein synthesis and secretion. These results provided insight into the possible pathogenic mechanism of type 2N VWD in Chinese patients carrying these mutations.     

Additional variant of type I von Willebrand disease

We introduce a family with a von Willebrand subgroup that has not been described before. All of the eight subjects examined had normal levels of factor VIII coagulant activity (FVIII:C), a moderate reduction in the level of von Willebrand factor antigen (VWF:Ag), which resulted in a high FVIII:C/VWF:Ag ratio, and normal crossed immunoelectrophoresis, with normal multimeric pattern. The ristocetin cofactor in plasma and platelets was very low. Bleeding time was prolonged in two subjects without clearcut linkage to laboratory findings. In addition, an abnormality of platelet aggregation in response to ADP was observed: a decreased initial response was followed by marked disaggregation.     

The use of desmopressin in von Willebrand disease: the experience of the first 30 years (1977–2007)

Summary.  The aim of the treatment for von Willebrand disease (VWD) is to correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion as a result of reduced and/or dysfunctional von Willebrand factor (VWF) and the abnormal coagulation expressed by low levels of factor VIII (FVIII). Correction of both deficiencies can be achieved by administering the synthetic peptide desmopressin (DDAVP) or, in cases unresponsive to this agent, the plasma concentrates containing VWF and FVIII (VWF/FVIII). DDAVP is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments, but the drug can be clinically useful also in other VWD types, including acquired von Willebrand syndrome (AVWS). A test dose of DDAVP at the time of diagnosis is recommended to establish the individual patterns of biological response and to predict clinical efficacy during bleeding and surgery. DDAVP is not effective in VWD type 3 and in severe forms of VWD 1 and 2. It can induce transient thrombocytopenia in patients with VWD type 2B. The results of several retrospective studies on the use of DDAVP in VWD management have been reported by many authors in different countries for the last 30 years. However, despite the widespread use of DDAVP in the treatment of VWD, there are only a few prospective clinical trials in a large number of cases on DDAVP efficacy and safety aimed at determining benefits and limits of this therapeutic approach. An investigator-driven observational prospective study on clinical efficacy of DDAVP in 200 patients with VWD types 1 and 2 has been recently organized: the effectiveness and safety of DDAVP will be evaluated prospectively for 24 months during bleeding episodes and minor or major surgeries in the VWD patients who were exposed to an infusion trial at enrollment.     

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.     

Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor

Type I von Willebrand disease (vWD) is characterized by equally low plasma concentrations of von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor (RiCof) and by the presence of all vWF multimers in sodium dodecyl sulfate (SDS)-agarose gel electrophoresis. For 17 patients (13 kindreds) diagnosed with these criteria, we have studied the platelet contents of vWF:Ag and RiCof and the changes of these in plasma after DDAVP infusion. Platelet vWF:Ag and RiCof were normal in four kindreds (called "platelet normal" subgroup); following 1-deamino- 8-D-arginine vasopressin; plasma vWF:Ag, RiCof and the bleeding time (BT) became normal. In six kindreds, platelet vWF:Ag and RiCof were equally low (platelet low); after DDAVP, plasma vWF:Ag and RiCof remained low, and the BT was prolonged. In three additional kindreds, platelets contained normal concentrations of vWF:Ag, but RiCof was very low (platelet discordant); even though a complete set of multimers was found in plasma and platelets, there was a relatively small amount of large multimers. After DDAVP, plasma vWF:Ag became normal, but RiCof remained low and the BT was very prolonged. These findings demonstrated that there can be an abnormal vWF (RiCof less than vWF:Ag) even in type I vWD, coexisting with a complete set of vWF multimers (platelet discordant); that the abnormal vWF can be shown more clearly in platelets than in plasma or else in plasma after DDAVP infusion; and that DDAVP normalizes the BT only in those patients with normal platelet levels of both vWF:Ag and RiCof (platelet normal).     

Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders

Desmopressin (DDAVP), a synthetic analogue of vasopressin has been successfully used in the treatment of type I von Willebrand's disease (VWD), mild factor VIII (FVIII) deficiency and intrinsic platelet function defects (PFDs) for almost three decades. However, there is limited published data documenting its efficacy and the reliability of circulating plasma FVIII:C as a surrogate marker of response to therapy in VWD. We report the haemostatic response to DDAVP in 133 consecutive patients (91 type I VWD, 20 mild FVIII deficiency and 22 PFDs). Minimal therapeutic response to DDAVP (0.3 microg/kg) was defined by normalization 30 min post- infusion of bleeding time for PFDs, factor VIII:C (FVIII:C) for mild haemophilia A, and von Willebrand factor antigen (VWF:Ag), von Willebrand factor functional activity (VWF:Ac) and FVIII:C for VWD. Nine out of 91 (10%) VWD patients failed to achieve minimal therapeutic response to DDAVP; plasma FVIII:C levels were an unreliable surrogate marker of DDAVP response as 6 out of 9 (67%) of these patients had normal post-infusion FVIII:C levels. Five out of the 20 (25%) patients with mild FVIII deficiency and 5 out of 22 (23%) patients with PFDs failed to achieve a minimal therapeutic response to DDAVP. DDAVP is an effective therapy in the majority of patients with type I VWD, PFDs and mild FVIII deficiency. The significant failure rate associated with this therapy supports the recent recommendations that response should be assessed in all patients at the time of diagnosis. FVIII:C is an unreliable guide of response to DDAVP in patients with VWD and therefore VWF:Ag and VWF:Ac should also be assessed. Failure to demonstrate the response of VWF:Ag, VWF:Ac and FVIII:C to DDAVP in patients with VWD is likely to increase the risk of haemorrhagic complications in patients with bleeding episodes or who are undergoing surgery.