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.     

von Willebrand disease and women's health

In 1926 von Willebrand described a bleeder family in Aland; this condition became known as von Willebrand disease (VWD). von Willebrand noted that "the trait seemed especially to be seen among the women." Today, the use of a pictorial bleeding assessment chart (PBAC) has enabled the prevalence of VWD to be established among women presenting with menorrhagia, as well as the documentation of this symptom in women with known VWD and the assessment of treatment response in menorrhagia. Treatments for menorrhagia include tranexamic acid, desmopressin (DDAVP) administered either intranasally or subcutaneously, the oral contraceptive pill, the "Mirena" coil (Schering Oy, Turku, Finland), and endometrial ablation. Von Willebrand factor (VWF) shows strong cyclical variation, with peak values occurring in the luteal phase. Although increased in pregnancy, levels of VWF decline postnatally and the incidence of both primary and secondary postpartum hemorrhage is high (20% to 25%). Baseline VWF levels less than 15 IU/dL are unlikely to reach greater than 50 IU/dL in the third trimester, and therefore prophylaxis with DDAVP or VWF-containing concentrate to cover delivery should be considered.     

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.     

The 80th anniversary of von Willebrand''s disease: history, management and research

The history of von Willebrand's disease (VWD) is fascinating because it demonstrates how good clinical observations, genetic studies and biochemical skills can improve basic understanding of a disease and its management. The continuous efforts of scientists and clinicians during the last 80 years have significantly improved the knowledge of von Willebrand factor (VWF) structure and function and the management of VWD. Diagnosis of phenotype and genotype is now available in many countries and treatment is becoming more specific according to the VWD type. Any therapeutic agents must correct the dual defect of haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional and low levels of factor VIII (FVIII) associated with VWF defects. Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it induces release of VWF from cellular compartments. Plasma virally inactivated VWF concentrates containing FVIII are effective and safe in patients unresponsive to DDAVP. There are advanced plans to develop a recombinant VWF but this product will require the concomitant administration of FVIII for the control of acute bleeds. Basic research studies on cellular biology, biochemistry and immunology have confirmed the role of VWF as a crucial participant in both haemostasis and thrombosis as its main biological activity is to support platelet adhesion-aggregation in the circulation. Retrospective and prospective clinical research studies, including bleeding history and laboratory markers for diagnosis as well as the use of DDAVP and VWF concentrates to manage or prevent bleeds in patients with VWD have been essential to provide general guidelines for VWD management. The large number of publications quoting VWD and VWF emphasizes the important role of VWF in medicine.     

Epidemiology, diagnosis, and management of von Willebrand disease in India

Von Willebrand disease (VWD) in all developing countries including India is considered a rare coagulation disorder, contrary to many reports from Western countries. Prevalence data based on hospital referrals identifies type 3 VWD as the most common subtype followed by type 1 and type 2. Approximately 60 to 70% cases of type 3 VWD are reportedly born of consanguineous marriages. The discriminatory diagnostic tests mainly include assays for factor (F)VIII:C and ristocetin-induced platelet agglutination and Von Willebrand factor (VWF) antigen either by immunoelectrophoresis or by enzyme-linked immunosorbent assay. VWD-type assisting tests like VWF collagen binding, VWF ristocetin cofactor assay, VWF-FVIII binding assay, and multimer analysis are occasionally used but not routinely applied in many laboratories. Among women, menorrhagia is an important presenting manifestation. Except for a handful of centers mainly in metropolitan cities, most laboratories in the remote parts of the country have no facilities for VWD-related investigations, resulting in occasional misdiagnoses of VWD as hemophilia A. Genetic diagnosis is being offered in two or three centers using the indirect linkage method in type 3 VWD, and efforts are continuing to implementing a direct mutation detection technique for routine practice in a few laboratories. Depending on the subtype or the severity of VWD, desmopressin, cryoprecipitate, fresh-frozen plasma, and factor VIII/VWF concentrates are used for management. Antifibrinolytic agents like epsilon-aminocaproic acid and tranexamic acid are widely used as an adjuvant therapy. In women with menorrhagia, oral contraceptives as a supplementary treatment are also being widely advocated to reduce bleeding. Products like danazol, ethenyl estradiol, thalidomide, and atorvastatin have been used in individual patients; acquired VWD associated with hypothyroidism has been managed successfully with thyroid hormone treatment. Both minor and major surgical procedures are performed in a few centers with judicious use of cryoprecipitate or FVIII concentrate containing VWF along with other supplementary therapeutic products to achieve adequate hemostasis. Awareness about the disease, establishment of the comprehensive coagulation laboratory, and treatment centers will be successful in increasing diagnosis of VWD and consequently better management of affected patients. This is likely to tilt the ratios of different VWD types, and VWD is likely to emerge as the most common of all coagulation disorders in the near future.     

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's disease: clinical management

Summary.  The aim of treatment of von Willebrand's disease (VWD) is to correct the dual defect of haemostasis, 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 VIII (FVIII). Desmopressin (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 type 1 and 2 are in progress to further explore its benefits and limits as 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 FVIII level between 50 and 150 U/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long term prophylaxis for recurrent bleedings.     

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.     

Prevalence of von Willebrand disease in women with iron deficiency anaemia and menorrhagia in Taiwan

Summary.  Iron deficiency anaemia (IDA) is a frequently encountered disease, which can be attributed to menorrhagia. Most female patients with von Willebrand disease (VWD) have menorrhagia. The aim of this study was to investigate the prevalence of VWD in women with both IDA and menorrhagia in Taiwan. From January to December 2005 and November 2006 to January 2007, 56 consecutive patients with both IDA and menorrhagia were enrolled in this study. Their median age was 41 years (range 18–53). IDA was diagnosed by anaemia plus either low ferritin or transferrin saturation. Menorrhagia was evaluated by patient's menses history. Both von Willebrand factor antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) were measured for each patient. Bleeding time (BT) and platelet function analyser (PFA)-100 assay were determined as ancillary tests. The VWD diagnosis was established if: (i) both VWF:Ag (<50%) and VWF:RCo (<50%) were low; (ii) either VWF:Ag or VWF:RCo was low plus prolonged BT or prolonged PFA closure times. VWF multimer analysis was performed for subtype confirmation of VWD. Nine of the 56 (16.1%) patients were identified to have VWD. VWD patients with menorrhagia might develop IDA at younger age (34.3 vs. 39.7, P  = 0.09) and had more IDA recurrence (75% vs. 16%, P  = 0.03) than those patients without VWD. Of the eight VWD patients with VWF multimer analyses, all were revealed to have type I VWD. Our study demonstrates that VWD was not uncommon in women with both IDA and menorrhagia in Taiwan.     

Comparative response of plasma VWF in dogs to up-regulation of VWF mRNA by interleukin-11 versus Weibel-Palade body release by desmopressin (DDAVP)

Recombinant human interleukin-11 (rhIL-11), a glycoprotein 130 (gp130)-signaling cytokine approved for treatment of thrombocytopenia, also raises von Willebrand factor (VWF) and factor VIII (FVIII) by an unknown mechanism. Desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]) releases stored VWF and FVIII and is used for treatment of VWF and FVIII deficiencies. To compare the effect of these 2 agents, heterozygous von Willebrand disease (VWD) and normal dogs were treated with either rhIL-11 (50 microg/kg/d subcutaneously x 7 days) or DDAVP (5 microg/kg/d intravenously x 7 days). The rhIL-11 produced a gradual and sustained elevation of VWF and FVIII levels in both heterozygous VWD and normal dogs while DDAVP produced a rapid and unsustained increase. Importantly, rhIL-11 treatment produced a 2.5- to 11-fold increase in VWF mRNA in normal canine heart, aorta, and spleen but not in homozygous VWD dogs, thus identifying a mechanism for elevation of plasma VWF in vivo. Moreover, dogs pretreated with rhIL-11 retain a DDAVP-releasable pool of VWF and FVIII, suggesting that rhIL-11 does not significantly alter trafficking of these proteins to or from storage pools. The half-life of infused VWF is unchanged by rhIL-11 in homozygous VWD dogs. These results show that rhIL-11 and DDAVP raise plasma VWF by different mechanisms. Treatment with rhIL-11 with or without DDAVP may provide an alternative to plasma-derived products for some VWD and hemophilia A patients if it is shown safe in clinical trials.     

Evidence-based recommendations on the treatment of von Willebrand disease in Italy

Background

von Willebrand disease (VWD) is the most common hereditary bleeding disorder affecting both males and females. It arises from quantitative or qualitative defects of von Willebrand factor (VWF) and causes bleeding of mucous membranes and soft tissues. The aim of treatment is to correct the dual defect of haemostasis caused by the abnormal/reduced VWF and the concomitant deficiency of factor VIII (FVIII).

Material and methods

This document contains evidence-based recommendations for the management of VWD compiled by AICE (the Italian Association of Haemophilia Centres). All the evidence supporting these recommendations are based on non-randomised comparative studies or case series, because randomised controlled clinical trials or meta-analyses are not available for this disease.

Results and conclusions

Desmopressin (DDAVP) is the treatment of choice for patients with type 1 VWD with FVIII and VWF levels of 10 U/dL or more, while VWF/FVIII concentrates are indicated for those who are unresponsive or insufficiently responsive to DDAVP (severe type 1, type 2 and 3 VWD). VWF concentrates devoid of FVIII, not yet licensed in Italy, may be considered for short-term prophylaxis in elective surgery or for long-term secondary prophylaxis.     

The factor VIII/von Willebrand factor complex: basic and clinical issues

Factor VIIII (FVIII) and von Willebrand factor (VWF) are two distinct but related glycoproteins that circulate in plasma as a tightly bound complex (FVIII/VWF). Their deficiencies or structural defects are responsible for the most common inherited bleeding disorders, namely hemophilia A (HA) and von Willebrand's disease (VWD). The VWF has a dual role in hemostasis: first it promotes platelet adhesion to thrombogenic surfaces as well as platelet-to-platelet cohesion during thrombus formation; second, it is the carrier for FVIII in plasma. FVIII acts as a co-factor to accelerate the activation of factor X by activated factor IX in the coagulation cascade. After many years of investigations, the molecular mechanisms of FVIII/VWF interactions are now well known and recent biochemical investigations have confirmed that VWF is a key partner for FVIII, playing significant roles in FVIII function, its production and its stabilization, in its conformation and immunogenicity. FVIII and VWF are both present in most plasma-derived FVIII/VWF concentrates used in clinical practice. FVIII/VWF concentrates can be classified into three main categories according to the degree of their purification. Intermediate-high purity plasma-derived concentrates containing FVIII/VWF currently in use since 1987 carry a low risk of transmitting blood-borne infections. Concentrate safety depends on the interaction of two factors: the decrease of viral plasma load and the increase of viral inactivation. These FVIII/VWF concentrates are currently used in type 3 VWD and in type 1 or 2 VWD patients who are unresponsive to desmopressin (DDAVP). More recently the presence of the physiologic FVIII/VWF complex has been considered to play an important role also in replacement therapy for patients with HA. The correct use of FVIII/VWF concentrates in VWD and HA have been reported in several national and international guidelines.     

Von Willebrand disease – the ‘Dos’ and ‘Don'ts’ in surgery

Von Willebrand disease (VWD) is the most common genetic bleeding disorder. VWD is caused by a deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates the initial adhesion of platelets at sites of vascular injury and binds and stabilises coagulation factor VIII (FVIII) in the blood. Prophylaxis of surgical bleeding in patients with VWD requires consideration of the individual situation, including the type of procedure and the bleeding rate, before decisions about treatment type, dose, duration and adjunctive therapy with antifibrinolytics or antithrombotic prophylaxis can be made. Although desmopressin (DDAVP)‐stimulated release of endogenous VWD is an effective treatment strategy in many patients, plasma concentrates containing VWF are the preferred option for most patients undergoing surgical procedures. Recommendations for the management of surgery in patients with VWD are summarised, including the severity of VWD and the type of the surgical procedure.     

Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders

Summary.  Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in paediatric patients with congenital bleeding disorders. Forty-one patients consisting of children with von Willebrand's disease (VWD, n  = 26) and platelet function defects (PFD, n  = 15) received DDAVP intravenously at a dosage of 0.3 μg/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen-binding activity (VWF:CB) and PFA 100^® closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two- to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non-responder, the CT shortened within 240 min after DDAVP. Two non-responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.     

Von Willebrand's disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment

BACKGROUND: Von Willebrand's disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency or abnormality of von Willebrand factor (VWF). VWF is a multimeric adhesive protein which plays an important role in primary hemostasis by promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions in high shear-rate conditions. It is also the carrier of factor VIII (FVIII), thus indirectly contributing to the coagulation process. VWD has a prevalence of about 1% in the general population, but the figure for clinically relevant cases is lower (about 100/million inhabitants). Bleeding manifestations are heterogeneous: mucosal bleeding is typical of all VWD cases but hemarthrosis and hematomas may also be present when FVIII levels are low. INFORMATION SOURCES: Most cases appear to have a partial quantitative deficiency of VWF (type 1 VWD) with variable bleeding tendency, whereas qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous. Type 3 VWD is rare and the patients have a moderate to severe bleeding diathesis because of the virtual absence of VWF, and a recessive pattern of inheritance. The diagnosis of VWD, especially type I, may be difficult, because the laboratory phenotype is highly heterogeneous and is confounded by the fact that factors outside the VWF gene (e.g., blood group) influence VWF levels. An array of tests is usually required to characterize the VWD types of the disorder and establish the best treatment modality. CONCLUSIONS: The aim of treatment is to correct the dual defect of hemostasis, i.e. abnormal coagulation expressed by low levels of FVIII and abnormal platelet adhesion expressed by the prolonged bleeding time (BT). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it corrects the FVIII/VWF levels and the prolonged BT in the majority of cases. 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 FVIII and VWF are the mainstay of treatment. These concentrates are clinically effective and safe, although they do not always correct the BT.     

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.     

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.     

Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD.     

Increased amounts of von Willebrand factor are bound to microparticles after infusion of desmopressin

Effects of desmopressin (DDAVP) in platelet disorders and primary haemostasis cannot be attributed solely to the increase in FVIII/VWF (von Willebrand factor), as VWF/FVIII concentrates have no effect in these circumstances. Microparticles (MP) can support haemostasis by expression of phospholipids, tissue factor and VWF on their surface. We hypothesized that significant amounts of VWF are bound to MP after DDAVP administration and that consequently depletion of MP should influence VWF:Ag and VWF:RCo plasma levels. Platelet‐poor plasma was either obtained well from healthy controls or before and after DDAVP administration from patients with von Willebrand's disease (type 1 or possible type 1) or patients with other bleeding disorders as controls. Concentrations of MP and VWF parameters were determined before and after MP depletion by different methods (magnetic bead selection, plasma microfiltration, ultracentrifugation). Platelet MP and VWF‐bearing MP were significantly increased after DDAVP. MP depletion by magnetic bead selection led to a significant reduction in VWF:Ag (?18.0%) and VWF:RCo (?27.7%) plasma levels without changes in VWF multimer composition. As results were similar for DDAVP control subjects, the amount of VWF bound to circulating microparticles was significantly higher after DDAVP administration compared with healthy controls (reduction ?11.7%). DDAVP leads to a release of microparticles and increases the amount of VWF bound to microparticles which might explain the clinical efficacy of DDAVP in platelet disorders.