Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance

SummaryAccelerated clearance of von Willebrand factor (VWF) has been recently identified as a major pathophysiologic mechanism inducing low VWF in some patients with von Willebrand disease (VWD). The frequency of bleeding and the best treatment of these patients have never been evaluated prospectively in large series of patients. It was the aim of the present study to prospectively evaluate clinical events of 60 heterozygous patients with VWD Vicenza (VWD-VI) carrying R1205H VWF mutation and 23 with C1130F mutation, both characterised by markedly increased VWF clearance. During 71 months of follow-up, 65% of patients with VWD-VI and 61% with C1130F required treatment. The rate of spontaneous bleeding requiring consultation/treatment was 7.5/100 patients-year in patients with C1130F mutation vs. 1.9/100 patients-year in those with R1205H (p=0.004). This difference persisted also by multivariate analysis adjusted for sex, age and blood group (hazard ratio [HR]=3.3 for C1130F, 95% confidence interval [CI] 1.16–9.27) and females were at greater risk of bleeding (HR=3, 95%CI 1.01–9.93) because of menorrhagia. Only 3/15 (20 %) women in fertile age with VWD-VI compared to 8/9 (89 %) with C1130F mutation required consultation/treatment for menorrhagia (iron supplementation, combined oral contraceptives, tranexamic acid). Almost all dental extractions, minor surgeries and deliveries occurring during follow-up were successfully managed with desmopressin. Major surgery required factor VIII/VWF concentrates, but a few cases benefited from desmopressin. In conclusion, similar to patients with type 1 VWD, also in patients with increased VWF clearance desmopressin maintains a major therapeutic role.

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How I treat type 2 variant forms of von Willebrand disease

Blood ◽

10.1182/blood-2014-08-551960 ◽

2015 ◽

Vol 125 (6) ◽

pp. 907-914 ◽

Cited By ~ 26

Author(s):

Alberto Tosetto ◽

Giancarlo Castaman

Keyword(s):

Von Willebrand Factor ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Major Surgery ◽

Bleeding Tendency ◽

Wide Range ◽

Deficiency Type ◽

Von Willebrand ◽

Willebrand Factor

AbstractType 2 von Willebrand disease (VWD) includes a wide range of qualitative abnormalities of von Willebrand factor structure and function resulting in a variable bleeding tendency. According to the current classification, 4 different subtypes can be identified, each with distinctive phenotypic and therapeutic characteristics. Current available laboratory methods allow a straightforward approach to VWD subtyping, and although the precise molecular characterization remains complex, it is not required for appropriate treatment of the vast majority of cases. Desmopressin can be useful only in a few type 2 cases compared with patients with actual quantitative deficiency (type 1), most often in variants with a nearly normal multimeric pattern (type 2M). However, since no laboratory test accurately predicts response to desmopressin, a trial test should always be performed in all type 2 VWD patients, with the exception of type 2B ones. Replacement therapy with plasma-derived von Willebrand factor-factor VIII concentrates represents the safe mainstay of treatment of all patients, particularly those not responding to desmopressin or requiring a sustained hemostatic correction because of major surgery or bleeding. A significant patient bleeding history correlates with increased bleeding risk and should be considered in tailoring the optimal antihemorrhagic prophylaxis in the individual patient.

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A Prospective Evaluation of Bleeding Tendency and Efficacy of Antihemorrhagic Treatments in Patients with Increased Von Willebrand Factor (VWF) Clearance (Von Willebrand Disease Vicenza AND C1130F Mutation).

Blood ◽

10.1182/blood.v112.11.3385.3385 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3385-3385 ◽

Cited By ~ 2

Author(s):

Giancarlo Castaman ◽

Alberto Tosetto ◽

Augusto B. Federici ◽

Francesco Rodeghiero

Keyword(s):

Tranexamic Acid ◽

Von Willebrand Disease ◽

Major Surgery ◽

Bleeding Tendency ◽

Pediatric Age ◽

Invasive Procedures ◽

Spontaneous Bleeding ◽

Surgical Interventions ◽

Von Willebrand

Abstract Background. von Willebrand disease Vicenza (VWD-VI) is characterized by severely reduced FVIII and VWF levels, the presence of ultra-large multimers in plasma, heightened response to desmopressin and increased clearance of VWF after desmopressin. Increased clearance of VWF has been identified in other VWF mutations, such as C1130F with similarly low FVIII/VWF levels as in VWD-VI. So far, the bleeding risk of these patients has not been formally established and it is unclear whether they need a different treatment approach. Aims, Design of the study, Patients and Methods. We prospectively evaluated the clinical history of 60 patients (32 M, 28 F) with VWD Vicenza (carrying R1205H mutation) and 23 patients (9 M, 14 F) with C1130F mutation, both characterized by increased VWF clearance. All in-hospital visits for bleeding symptoms, treatments and prophylaxis prior to invasive procedures were recorded together with home-treatments. All the remaining patients were contacted yearly to update their bleeding symptoms, if any. The study lasted from January 2002 to December 2007. Results. During follow-up, 21/60 (35 %) and 9/23 (39 %) of patients with VWD-VI or C1130F respectively did not require treatment for bleeding or prior to invasive procedures. Ten patients with VWD-VI and 5 with C1130F had 1 to 3 tooth extraction instances treated with a single desmopressin infusion plus oral tranexamic acid for 5 days, without mishap. A single patient carrying out dental extraction without any prophylaxis had bleeding promptly stopped by a single desmopressin infusion. Four women with VWD-VI and 6 with C1130F had 1 or 2 pregnancies during follow-up, and successfully completed delivery by using two or three desmopressin infusions over 24-48 hours after vaginal delivery. Epistaxis requiring consultation or treatment was almost limited to pediatric age and a single adult patient only required treatment for an isolated episode. A single post-traumatic joint bleeding required a successful treatment with desmopressin. Only 3/15 (20 %) women in fertile age with VWD-VI required treatment for menorrhagia (iron suppletion, combined oral estroprogestinic pill, tranexamic acid) compared to 8/9 (89 %) with C1130F mutation. Most minor surgical interventions were successfully covered with desmopressin while major surgery required FVIII/VWF concentrates since prolonged hemostasis was required. Conclusions. Spontaneous bleeding in patients with VWD-VI and C1130F appeared to be mainly limited to epistaxis in pediatric age and menorrhagia in females. Most of clinical situations are successfully manageable with desmopressin, as usually occurs for other type 1 VWD patients, and despite the short FVIII and VWF half-life post-infusion.

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Mutations in von Willebrand Factor Multimerization Domains Are not a Common Cause of Classical Type 1 von Willebrand Disease

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614853 ◽

1999 ◽

Vol 82 (11) ◽

pp. 1446-1450 ◽

Cited By ~ 4

Author(s):

Anthony Cumming ◽

Charles Hay ◽

Stephen Keeney

Keyword(s):

Von Willebrand Factor ◽

Full Range ◽

Von Willebrand Disease ◽

Heteroduplex Analysis ◽

Common Mechanism ◽

Classical Type ◽

Bleeding Tendency ◽

Von Willebrand ◽

Willebrand Factor

SummaryType 1 von Willebrand disease (vWD) is an autosomal dominant bleeding disorder of variable penetrance. It is characterised by a mild to moderate bleeding tendency and a quantitative deficiency of von Willebrand factor (vWF) with the full range of vWF multimers. Few mutations have been described which account for the mode of inheritance in dominant vWD type 1. We screened the vWF multimerization domains (regions D1-D3 of the vWF gene) of 12 unrelated patients with dominant vWD type 1 to investigate the hypothesis that multimerization of vWF sub-units may be inhibited or reduced by a “dominant negative” mechanism. Platelet-derived RNA was reverse transcribed and the resulting vWF cDNA amplified by the polymerase chain reaction (PCR) in a series of overlapping fragments. These were subjected to a combination of single-strand conformation polymorphism (SSCP) and heteroduplex analysis. This approach identified mobility shifts on acrylamide gels that represented 12 distinct SSCP and/or heteroduplex patterns in our patient group. DNA sequencing of the region encompassing each mobility shift showed these variants to represent previously described polymorphisms within the vWF coding sequence. Examination in all 12 patients for the previously described G3389T and T3445C mutations proved negative. The molecular pathology of classical type 1 vWD remains enigmatic, mutations having been identified in only a small minority of patients. A common mechanism underlying this disease state has still to be elucidated.

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The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651575 ◽

1993 ◽

Vol 69 (02) ◽

pp. 173-176 ◽

Cited By ~ 5

Author(s):

Anna M Randi ◽

Elisabetta Sacchi ◽

Gian Carlo Castaman ◽

Francesco Rodeghiero ◽

Pier Mannuccio Mannucci

Keyword(s):

Von Willebrand Factor ◽

Autosomal Dominant ◽

Genetic Defect ◽

Von Willebrand Disease ◽

Type I ◽

Bleeding Tendency ◽

Factor Gene ◽

Low Levels ◽

Von Willebrand ◽

Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

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Autoantibody Selectively Inhibits Binding of von Willebrand Factor to Glycoprotein Ib. Recognition Site Is Located in the A1 Loop of von Willebrand Factor

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656047 ◽

1997 ◽

Vol 77 (04) ◽

pp. 760-766 ◽

Cited By ~ 4

Author(s):

Hiroshi Mohri ◽

Etsuko Yamazaki ◽

Zekou Suzuki ◽

Toshikuni Takano ◽

Shumpei Yokota ◽

...

Keyword(s):

Von Willebrand Factor ◽

Significant Inhibition ◽

Von Willebrand Disease ◽

Recognition Site ◽

Severe Bleeding ◽

Bleeding Tendency ◽

Virtual Absence ◽

Heavy Chains ◽

Von Willebrand ◽

Willebrand Factor

SummaryA 20-year-old man with severe von Willebrand disease recently presented a progressive bleeding tendency, characterized recurrent subcutaneous hemorrhages and cerebral hemorrhage. Mixing and infusion studies suggested the presence of an inhibitor directed against vWF:RCo activity of von Willebrand factor (vWF) without significant inhibition of the FVIII:C. The inhibitor was identified as an antibody of IgG class. The inhibitor inhibited the interaction of vWF in the presence of ristocetin and that of asialo-vWF with GPIb while it partially blocked botrocetin-mediated interaction of vWF to GPIb. The inhibitor reacted with native vWF, the 39/34kDa fragment (amino acids [aa] 480/ 481-718) and the recombinant vWF fragment (MalE-rvWF508-704), but not with Fragment III-T2 (heavy chains, aa 273-511; light chains, aa 674-728). A synthetic peptide (aa 514-542) did not inhibit vWF-inhibitor complex formation. We conclude that this is the first autoantibody of class IgG from human origin that recognizes the sequence in the A1 loop of vWF, resulting in a virtual absence of functional vWF and a concomitant severe bleeding tendency although recognition site is different from the residues 514-542 which is crucial for vWF-GPIb interaction.

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Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1722864 ◽

2021 ◽

Vol 47 (02) ◽

pp. 192-200

Author(s):

James S. O'Donnell

Keyword(s):

Von Willebrand Factor ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Personalized Treatment ◽

Treatment Plans ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor

AbstractThe biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

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Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen

Blood ◽

10.1182/blood.v84.10.3378.3378 ◽

1994 ◽

Vol 84 (10) ◽

pp. 3378-3384 ◽

Cited By ~ 61

Author(s):

PJ van Genderen ◽

T Vink ◽

JJ Michiels ◽

MB van 't Veer ◽

JJ Sixma ◽

...

Keyword(s):

Von Willebrand Factor ◽

Binding Activity ◽

Von Willebrand Disease ◽

Low Grade ◽

Bleeding Tendency ◽

Glycoprotein Ib ◽

Acquired Von Willebrand Disease ◽

Recurrent Epistaxis ◽

Von Willebrand ◽

Willebrand Factor

Abstract An 82-year-old man with a low-grade malignant non-Hodgkin lymphoma and an IgG3 lambda monoclonal gammopathy presented a recently acquired bleeding tendency, characterized by recurrent epistaxis, easy bruising, and episodes of melena, requiring packed red blood cell transfusions. Coagulation studies showed a von Willebrand factor (vWF) defect (Ivy bleeding time, > 15 minutes; vWF antigen [vWF:Ag], 0.08 U/mL; ristocetin cofactor activity [vWF:RCoF], < 0.05 U/mL; collagen binding activity [vWF:CBA], 0.01 U/mL; absence of the high molecular weight multimers of vWF on multimeric analysis). Mixing experiments suggested the presence of an inhibitor directed against the vWF:CBA activity of vWF without significantly inhibiting the FVIII:C, vWF:Ag, and vWF:RCoF activities. The inhibitor was identified as an antibody of the IgM class by immunoabsorption of vWF and inhibitor-vWF complexes from the plasma of the patient. Subsequent immunoprecipitation experiments using recombinant fragments of vWF showed that the inhibitor reacted with both the glycoprotein Ib binding domain (amino acids [aa] 422–826) and the A3 (aa 909–1112) domain of vWF, but not with the A2 (aa 716–908) or D4 (aa 1183–1535) domains. We conclude that the IgM autoantibody inhibits the vWF:CBA activity by reacting with an epitope present on both the glycoprotein Ib and A3 domains of vWF.

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