scholarly journals Replacement Therapy in Patients with Von Willebrand Disease—Indications and Monitoring

2019 ◽  
Vol 39 (04) ◽  
pp. 326-338
Author(s):  
Ulrike Nowak-Göttl ◽  
Wolfgang Miesbach ◽  
Jürgen Koscielny ◽  
Carl-Erik Dempfle ◽  
Marc Maegele ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Von Willebrand Disease ◽  
Spontaneous Bleeding ◽  
Surgical Interventions ◽  
Bleeding Episodes ◽  
Repeated Dosing ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Trough Levels ◽  
Very High

AbstractIn patients with von Willebrand disease (VWD), replacement therapy may be indicated in the case of spontaneous bleeding, surgical interventions and injuries/trauma or as a prophylaxis of spontaneous bleeding episodes. The deficient von Willebrand factor (VWF) is replaced with or without factor VIII (FVIII). Dual VWF/FVIII concentrates can be beneficial in the case of low FVIII level, while repeated dosing may lead to very high FVIII levels, with a potential thrombogenic effect in individual VWD patients. An excessive FVIII:C increase can be limited by using a VWF product with a low level of FVIII, achieving a haemostatic adequate FVIII:C increase after 6 to 12 hours. Replacement therapy in patients with VWD shall be individualised considering VWD type, history and risk of bleeding and risk of thrombosis, as well as indication and the individually variable VWF and FVIII increase. Deviations from the dosages and minimum trough levels mentioned in guidelines or recommendations can be considered in justified cases. The objective of this review is to provide recommendations for specific constellations of replacement therapy based on the VWD-specific guidelines available in Europe, the available evidence, own experiences and the consensus of the interdisciplinary German author group.

scholarly journals A Unique Case of Type 3 Von Willebrand Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5031-5031
Author(s):  
Mamatha Mandava ◽  
John Lazarchick ◽  
Emily Curl ◽  
Shayla Bergmann
Keyword(s):  
Replacement Therapy ◽  
Von Willebrand Factor ◽  
Conflicts Of Interest ◽  
Von Willebrand Disease ◽  
Compound Heterozygosity ◽  
Increased Risk ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder worldwide. Genetic mutations in the von Willebrand gene may result in either quantitative (Types 1 and 3 vWD) or qualitative defects (Type 2 vWD) of von Willebrand Factor (vWF). Type 3 is the rarest and most severe form of vWD, resulting in a virtual absence of vWF. Type 3 vWD follows autosomal recessive inheritance and is most often reported in patients who are homozygous for the same gene mutation. We report a patient with type 3 vWD who inherited two different mutations, one from each parent, resulting in compound heterozygosity. Case: Our patient, now a 2 year old female, initially presented with prolonged bleeding lasting approximately 5 hours at the injection site of her 2 month immunizations. Labs on initial presentation showed a normal WBC count, hemoglobin, hematocrit, and platelet count, with normal levels of Factor IX, XI, and XII activity. PTT was prolonged at 59 (reference range 23.3-35.7) with a normal INR. Von Willebrand panel showed markedly decreased Factor VIII (2%), vWF antigen (6%), and vWF activity (8%). VWF multimers were absent, consistent with a diagnosis of type 3 vWD. VWF gene sequence analysis showed two pathologic variants, one on each allele: c2345delC in exon 18 and a deletion within exon 6. Her parents, both 27 years old and with no history of abnormal bleeding, are non-consanguineous. Analysis of parents for vWD revealed that mother is heterozygous for the c2345delC variant and the patient's father is heterozygous for the deletion within exon 6 of the VWF gene. The patient's older sibling who is now 4 years old developed unusual petechiae and bruising after an altercation at school, his testing was positive for only the maternal mutation, resulting in a diagnosis of Type 1 vWD, and a younger brother was negative for both mutations. Our patient has subsequently suffered recurrent episodes of bruising, gingival bleeding, and poor tissue healing and currently requires replacement therapy (prophylaxis) with Humate-P three times each week and additionally as needed. Discussion: Type 3 vWD is quite rare, with a prevalence ranging from 0.1-5.3 per million. Our case is especially interesting due to the unique inheritance pattern resulting in our patient's type 3 vWD phenotype. Type 3 vWD cases are often described in patients homozygous for a mutation in the VWF gene, frequently as a result of consanguinity. Our patient inherited a unique variant from each parent, resulting in heterozygous expression of two defective VWF alleles (compound heterozygosity). Our patient's maternally inherited defect c2435delC in exon 18 is the variant found in the original vWD family described by Dr. Erik von Willebrand in 1926. Less is understood about the paternally inherited defect of a deletion in exon 6 of VWF. In our patient's family, because each parent is heterozygous for a mutation in the VWF gene, future children have a 75% chance of inheriting at least one mutation, and a 25% chance of inheriting both mutations, leading to Type 3 vWD. Type 3 vWD patients have impaired endogenous synthesis of functional vWF, thus therapies such as desmopressin, used in other types of vWD to stimulate secretion of endogenous vWF, are ineffective. Instead, first-line treatment in Type 3 is replacement therapy with Humate-P as needed during bleeding episodes and/or as prophylaxis. Humate P is VWF/FVIII concentrate obtained from pooled human plasma from many carefully screened plasma donors and contains the clotting proteins VWF and FVIII. Humate-P has a VWF:FVIII ratio of approximately 2.4:1. Complications of therapy include the rare development of anti-vWF alloantibodies, which most often occurs in patients with partial or complete VWF gene deletions. Our patient has received aminocaproic acid for minimal bleeding episodes and due to her severe intensity of disease and age of increased risk of injuries had received plasma derived vWF/FVIII concentrates for multiple episodes of moderate bleeding. She has not developed antibodies yet, but is at high risk. The rWVF (recombinant von Willebrand factor) offers new perspective in treatment of vWD more so with type 3 disease. It is a homogenous protein synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line, retains its intact multimer pattern because it is never exposed to proteases(ADAMTS13) which can degrade it. The rVWF is currently in phase 3 clinical trials Disclosures No relevant conflicts of interest to declare.

Treatment of Von Willebrand Disease

2001 ◽  
Vol 86 (07) ◽  
pp. 149-153 ◽  
Author(s):  
Pier Mannuccio Mannucci
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Spontaneous Bleeding ◽  
Primary Hemostasis ◽  
Bleeding Prophylaxis ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryIn von Willebrand disease, there are two main options for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1, who account for approximately 70 to 80 per cent of all cases with the disease. This non-transfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor three- to fivefold and thereby transiently corrects both the intrinsic coagulation and primary hemostasis defects. In patients with the more severe type 3 and in the majority of those with type 2 desmopressin is not effective or is contraindicated, so that it is usually necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Concentrates treated with virus inactivation methods should be preferred to cryoprecipitate because they are equally effective and perceived as safer.

scholarly journals Prophylactic management of patients with von Willebrand disease

2021 ◽  
Vol 12 ◽  
pp. 204062072110640
Author(s):  
Massimo Franchini ◽  
Omid Seidizadeh ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Von Willebrand Disease ◽  
Spontaneous Bleeding ◽  
Excessive Bleeding ◽  
Increased Risk ◽  
Bleeding Episodes ◽  
Males And Females ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Short Term Prophylaxis

Von Willebrand disease, the most common inherited bleeding disorder that affects both males and females, is due to quantitative or qualitative defects of the multimeric glycoprotein von Willebrand factor, which cause mucous membrane bleeding but also soft tissue bleeding owing to the secondary deficiency of factor VIII. The aim of treatment is to correct this dual defect of hemostasis. In addition to the episodic management of bleeding episodes, therapy includes their short- or long-term prevention. Short-term prophylaxis is mainly warranted in order to provide effective hemostatic coverage to patients undergoing surgery or invasive procedures and to affected women at the time of delivery or during menstruations associated with excessive bleeding. The aim of long-term prophylaxis is to prevent bleeding in particular categories of patients at increased risk of frequent and spontaneous bleeding in the joints, nose, and gastrointestinal tract.

How I treat patients with von Willebrand disease

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 1915-1919 ◽  
Author(s):  
Pier Mannuccio Mannucci
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Spontaneous Bleeding ◽  
Primary Hemostasis ◽  
Bleeding Prophylaxis ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Von Willebrand disease (vWD) is a frequent inherited disorder of hemostasis that affects both sexes. Two abnormalities are characteristic of the disease, which is caused by a deficiency or a defect in the multimeric glycoprotein called von Willebrand factor: low platelet adhesion to injured blood vessels and defective intrinsic coagulation owing to low plasma levels of factor VIII. There are 2 main options available for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1 vWD, who account for approximately 70% to 80% of cases. This nontransfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor 3 to 5 times and thereby corrects both the intrinsic coagulation and the primary hemostasis defects. In patients with the more severe type 3 and in most patients with type 2 disease, desmopressin is ineffective or is contraindicated and it is usually necessary to resort to plasma concentrates containing both factor VIII and von Willebrand factor. Concentrates treated with virucidal methods should be preferred to cryoprecipitate because they are equally effective and are perceived as safer.

scholarly journals Evolution of replacement therapy for von Willebrand disease: From plasma fraction to recombinant von Willebrand factor

Blood Reviews ◽  
2019 ◽  
Vol 38 ◽  
pp. 100572 ◽  
Author(s):  
Flora Peyvandi ◽  
Peter Kouides ◽  
Peter L. Turecek ◽  
Edward Dow ◽  
Erik Berntorp
Keyword(s):  
Replacement Therapy ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Plasma Fraction ◽  
Von Willebrand ◽  
Willebrand Factor

Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 450-456 ◽  
Author(s):  
Pier M. Mannucci ◽  
Juan Chediak ◽  
Wahid Hanna ◽  
John Byrnes ◽  
Marlies Ledford ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
High Purity ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Invasive Procedures ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate—one virally inactivated with solvent detergent, the other with an additional heat-treatment step—were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.

scholarly journals [Cost-minimization analysis of replacement therapy in the treatment of von Willebrand disease]

2016 ◽  
Vol 17 (2) ◽  
pp. 59-65
Author(s):  
Giancarlo Castaman
Keyword(s):  
Replacement Therapy ◽  
Cost Minimization ◽  
Von Willebrand Disease ◽  
Major Surgery ◽  
Spontaneous Bleeding ◽  
Cost Minimization Analysis ◽  
Italian National Health Service ◽  
Minor Surgery ◽  
Italian National Health ◽  
Von Willebrand

BACKGROUND: Replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates represents an effective approach for patients with von Willebrand disease (VWD) who are unresponsive to desmopressin. However, various concentrates are available, with heterogeneous VWF content and VWF/FVIII ratio.AIM: To compare the costs associated to the replacement therapy with VWF/FVIII concentrates in Italy.METHODS: A cost-minimization analysis was performed to compare the pharmaceutical costs per patient of alternatives available for replacement therapy of VWD in the prospective of the Italian National Health Service. For each alternative the analysis calculated the number of vials, and relative costs, required to reach the target levels of VWF:RCo in patients who undergone to major surgery, minor surgery, spontaneous bleeding and prophylaxis.RESULTS: Haemate P® is associated with the lowest FVIII dosage, numbers of vials used and costs in all the clinical situations and at all the dosages considered. With Haemate P® the average costs in major surgery, minor surgery, spontaneous bleeding, and prophylaxis was € 710.94, € 592.45, € 473.96, and € 592.45, respectively. While the costs associated to Fanhdi®, Wilate®, and Wilfactin® was: € 1,309.28, € 1,071.23, € 952.20, and € 1,190.25; € 1,512.45, € 1,344.40, € 1,176.35, and € 1,344.40; € 3,814.09, € 3,269.22, € 3,269.22, and € 3,814.09.CONCLUSIONS: Treatment with Haemate P®, which presents a low FVIII content, allows to reach the target level of VWF:RCo with a lower number of vials and lower costs for the NHS.[Article in Italian]

Acquired Factor VIII and von Willebrand Factor (aFVIII/VWF) Deficiency and Hypothyroidism in a Case With Hypopituitarism

2008 ◽  
Vol 16 (1) ◽  
pp. 107-109 ◽  
Author(s):  
Miriam C. Oliveira ◽  
Caroline K. Kramer ◽  
Caroline P. Marroni ◽  
Carolina G.S. Leães ◽  
Luciana Viana ◽  
...  
Keyword(s):  
Hormone Replacement Therapy ◽  
Factor Viii ◽  
Replacement Therapy ◽  
Von Willebrand Factor ◽  
Hormone Replacement ◽  
Von Willebrand Disease ◽  
Rare Association ◽  
Central Origin ◽  
Von Willebrand ◽  
Willebrand Factor

This article reports a female who presented with bleeding, acquired factor VIII and von Willebrand factor (aFVIII-VWF) deficiency, and central deficiency in the thyroid and adrenal axis (Sheehan’s syndrome). After starting hormone replacement therapy, relief of bleeding manifestations was associated with correction of both FVIII and VWF to normal. This report draws attention to a rare association between the acquired form of von Willebrand disease and hypothyroidism of central origin.

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