scholarly journals Elevated von Willebrand factor levels during heavy menstrual bleeding episodes limit the diagnostic utility for von Willebrand disease

2021 ◽  
Author(s):  
Megan C. Brown ◽  
Michael H. White ◽  
Rachel Friedberg ◽  
Kalinda Woods ◽  
Krista Childress ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Heavy Menstrual Bleeding ◽  
Menstrual Bleeding ◽  
Diagnostic Utility ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals The spectrum and severity of bleeding in adolescents with low von Willebrand factor–associated heavy menstrual bleeding

2020 ◽  
Vol 4 (13) ◽  
pp. 3209-3216 ◽  
Author(s):  
Lakshmi Srivaths ◽  
Charles G. Minard ◽  
Sarah H. O’Brien ◽  
Allison P. Wheeler ◽  
Eric Mullins ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Assessment Tool ◽  
Combined Therapy ◽  
Laboratory Data ◽  
Heavy Menstrual Bleeding ◽  
Menstrual Bleeding ◽  
Bleeding Complications ◽  
Eligibility Criteria ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Low von Willebrand factor (VWF) in adults is associated with significant bleeding, most notably heavy menstrual bleeding (HMB) and postpartum hemorrhage, although this has not been characterized in adolescents. The objectives of this analysis of a multicenter single arm observational cohort study in adolescents with low VWF–associated HMB were to describe the bleeding phenotype, HMB severity, and related complications. Eligibility criteria included postmenarchal females <21 years of age with HMB (Pictorial Blood Assessment Chart [PBAC] score >100) and low VWF (2 values of VWF activity ≥30 and ≤50 IU/dL). Patients diagnosed with other bleeding disorders were ineligible. Clinical phenotype data, including PBAC and Bleeding Assessment Tool (BAT) scores, laboratory data, and HMB management/outcome details, were extracted. Patient demographics and clinical characteristics were summarized as medians with minimum/maximum values or frequencies with percentages. Groups were compared using a Wilcoxon rank-sum test or Fisher’s exact test. A total of 113 patients met inclusion criteria, and 2 were excluded. Ninety four percent had a significant bleeding phenotype (BAT score >2), with predominantly mucocutaneous bleeding (32%-44%), postprocedural/surgical bleeding (15%), and severe HMB (BAT HMB domain score ≥2; 90%). Bleeding complications included iron deficiency (60%), anemia (21%), transfusion (12%), and hospitalization (10%). Desmopressin challenge response in subjects tested was good and sustained. Several (48%) required combined therapy for HMB (hormonal/hemostatic), and one third did not show improvement despite therapy. Our results suggest that adolescent females with low VWF have a significant bleeding phenotype and resultant complications warranting a focus on prompt diagnosis, appropriate therapy, and prevention of complications.

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 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.

Safety and Efficacy of Continuous Infusion of a Combined Factor VIII – von Willebrand Factor (vWF) Concentrate (Haemate-P™) in Patients with von Willebrand Disease

1999 ◽  
Vol 81 (02) ◽  
pp. 229-233 ◽  
Author(s):  
Aharon Lubetsky ◽  
Sam Schulman ◽  
David Varon ◽  
Uri Martinowitz ◽  
Gili Kenet ◽  
...  
Keyword(s):  
Factor Viii ◽  
Continuous Infusion ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Safety And Efficacy ◽  
Intermittent Bolus ◽  
Surgical Bleeding ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryWe studied the safety and efficacy of treatment with continuous infusion of a von Willebrand factor (vWF) concentrate Haemate-P in patients with von Willebrand disease (vWD). Three patients with mild and 5 patients with severe forms of vWD, were treated with continuous infusion of Haemate-P by minipump. The indications for treatment were: to prevent bleeding during 9 surgical procedures or 1 vaginal delivery in 6 patients and to treat 2 bleeding episodes in 2 patients. The patients were monitored daily for factor VIII (FVIII:C) and ristocetin cofactor (vWF:RCo) levels and the infusion rate was adjusted to maintain the desired therapeutic level of vWF:RCo. The treatment was effective in preventing surgical bleeding and controlling bleeding episodes. All factor VIII:C and most of the vWF:RCo levels measured during the study period were above the target therapeutic levels. A significant decrease in clearance of FVIII:C and vWF:RCo was observed over the treatment period. Haemate-P consumption averaged 24.3 ± 7.9 vWF:RCo U/kg/day which is approximately half the expected dose had intermittent bolus injections been used. We suggest that continuous Haemate-P infusion is superior to intermittent bolus injections for the treatment of vWD patients by virtue of its efficiency, simplicity and considerable savings.

scholarly journals DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1972-1975 ◽  
Author(s):  
M Cattaneo ◽  
M Moia ◽  
P Delle Valle ◽  
P Castellana ◽  
PM Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Double Blind ◽  
Prolonged Bleeding ◽  
Primary Hemostasis ◽  
Prolonged Bleeding Time ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.

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.

DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1972-1975
Author(s):  
M Cattaneo ◽  
M Moia ◽  
P Delle Valle ◽  
P Castellana ◽  
PM Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Double Blind ◽  
Prolonged Bleeding ◽  
Primary Hemostasis ◽  
Prolonged Bleeding Time ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.

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.

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