Low Von Willebrand Factor Antigen Research Articles

Initial von Willebrand factor antigen values in adolescent females predict future values.

Diagnosing von Willebrand Disease (VWD) in adolescent females is challenging as menstruation and physiologic stress elevate von Willebrand factor (VWF) laboratory values. To develop a VWF prediction model for adolescent females based on initial VWF results. We identified female patients aged 9 to 21 years with any VWF laboratory test over a 5-year period (2017-2021) at any Texas Children's Hospital facility. Patient demographics, VWF testing, haemoglobin concentration, serum ferritin and site of clinical testing were collected (initial and subsequent laboratory evaluations). A Bayesian linear regression model was developed. Prediction intervals were analysed to identify thresholds for patients in whom repeat testing was unlikely to identify low VWF levels (<50%), consistent with VWD. A total of 6125 adolescent females underwent VWF testing; 1204 (19.7%) had repeat testing. Based on the prediction model, initial VWF antigen values of 80%, 90% and ≥100% carried a 92.6%, 96.6% and ≥98.0% probability of having repeat normal repeat VWF values, respectively.Subjects assessed in outpatient adolescent medicine or gynaecology clinics were more likely to have low VWF values compared to those assessed in the acute care setting (p<.001). Median presenting haemoglobin and serum ferritin were 12.4g/dL and 13ng/mL, respectively and were similar in those with normal versus low VWF antigen values. Repeat testing in adolescent females whose initial VWF antigen values are ≥90% is unlikely to identify additional patients with VWD. Iron deficiency screening should be performed in all adolescent females.

To Repeat or Not Repeat, That Is the Question: Von Willebrand Testing in Adolescent Girls with Heavy Menstrual Bleeding

Heavy menstrual bleeding (HMB) is often the initial manifestation of a bleeding disorder in adolescent females. Von Willebrand disease (VWD) is the most common bleeding disorder, yet diagnosing VWD in HMB is challenging given that menstruation, acute illness, and physiologic stress all elevate von Willebrand factor (VWF) laboratory values. Thus, the interpretation of initial VWF results may be challenging, and the need for repeat VWF testing in this population may be unclear. The aims of this study were to understand VWD diagnostic testing patterns in adolescent females evaluated within the Texas Children's Hospital (TCH) network and to develop a prediction model to determine whether repeat testing was indicated based on initial VWF testing results. Female patients aged 9 to 21 years who had any VWF laboratory test over a 5-year period (January 1, 2017 through December 31, 2021) at a TCH facility (greater Houston metroplex) were identified. Data collection included patient demographics, VWF-related testing (antigen and activity [ristocetin cofactor or glycoprotein Ib]), factor VIII activity, hemoglobin concentration and serum ferritin. Both initial and subsequent laboratory evaluations were collected. The site of clinical testing was also identified, including both acute care settings (emergency department, inpatient, and critical care), and outpatient settings (adolescent medicine, gynecology, hematology, otolaryngology, other outpatient TCH primary care clinics). To ensure that subsequent laboratory testing was not mistaken as the initial testing within the cohort, patients who underwent VWF laboratory testing from 2010 to 2016 were excluded. VWF levels obtained after the administration of VWF replacement products were also removed from the data set. Based on the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, and with the presumption that adolescents with HMB met the criteria for abnormal bleeding, we analyzed the need to repeat VWF testing to identify any patient with a low VWF antigen level consistent with Type 1 VWD, defined as <50%. A Bayesian linear regression model was developed to predict follow-up VWF antigen levels using the initial levels. Prediction intervals were analyzed to identify thresholds for patients who may not require retesting. This study was approved by the Baylor College of Medicine Institutional Review Board. A total of 6,125 adolescent females underwent VWD testing at a TCH facility during the study period; 1,204 (19.7%) had repeat VWF antigen values performed and were included in the analysis (TABLE). Of those, 1,037 subjects (86.1%) had normal VWF values (≥50%) on both initial and repeat testing. Seventy-five subjects (6.2%) had low VWF antigen values on both initial and repeat testing. Ninety-two subjects had discrepant initial and repeat testing. Forty-seven (3.9%) had low initial VWF antigen values that normalized on subsequent testing. Forty-five (3.7%) had normal initial VWF values that subsequently fell below 50%. Based on our prediction model, in subjects with initial VWF antigen values of ≥80% there was ≥97% probability of having normal repeat VWF values. Values of ≥100% carry a 99.4% probability of having normal repeat VWF testing (FIGURE). No association was identified between age and VWF antigen level. Subjects assessed in outpatient adolescent medicine or gynecology clinics were more likely to have low VWF values (on any testing) whereas subjects with normal values were more frequently assessed in the acute care settings (P<0.001). The median serum ferritin and hemoglobin values in the cohort were 13 ng/ml and 12.8 g/dl, respectively, without a significant difference between those with normal versus low VWF antigen values. Repeat testing in adolescent females whose initial VWF antigen testing values are 80% and higher is unlikely to identify more patients with VWF values below 50%. In this cohort, subjects undergoing hemostatic evaluation, presumably for HMB, by adolescent medicine or gynecology providers were more likely to identify abnormal VWD testing compared to the acute care setting. Iron deficiency screening should be considered for all adolescent females with HMB and not just those girls with a confirmed bleeding disorder. Additional studies are needed to determine the effects of iron deficiency and anemia on VWD laboratory testing in adolescent females with HMB and to validate the accuracy of the prediction model. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Determination of von willebrand factor antigen in patients with undiagnosed menorrhagia

This prospective study is about screening of von willbrand antigen in patients with undiagnosed menorrhagia, because the underlying cause may be haematological disorder in 50% of cases. To estimate the incidence of von willbrand disease in patients with undiagnosed menorrhagia. During the period of 2 months from February to april 2005, total of 50 patients were included in this study that were referred to Al-yarmok teaching hospital. The age range of these patients was 18-45 year. Full history and physical examination done, ultrasound examination to exclude local causes of menorrhagia, thyroid function done. 30 healthy volunteer age matched were included as control group. For each patient and control group the following tests were done: Bleeding time, Prothrombin time, Activated partial thromboplastin time, Factor 8 level, Von willbrand factor antigen level.Results1.There was no obvious or statistically significant difference in mean bleeding time and activated partial thromboplastine time observed between healthy controls and patients with menorrhagia.2.The mean Von Willebrand factor antigen (%) was significantly lower in patients with menorrhagia compared with healthy controls.3.The mean Von Willebrand factor antigen was slightly lower at the older age group compared to younger age group.4.The proportion of patients with prolonged activated partial thromboplastine time was obviously higher among those with abnormally low Von Willebrand factor antigen compared to those with acceptable level.5.The relative frequency of cases with abnormally low factor VIII activity was higher among subjects with other bleeding manifestations compared to those with no manifestations. 6.The relative frequency of cases with abnormally low factor VIII activity was higher among subjects with positive family history of bleeding tendency. 7.The relative frequency of cases with abnormally low Von Willebrand factor was obviously higher among subjects with other bleeding manifestations compared to those with no bleeding manifestations, also it was higher among cases with positive family history of bleeding tendency and those with past history of severe bleeding episodes.Conclusions: The prevalence of Von Willebrand disease is increased in women with menorrhagia. So it is reasonable to believe that Von Willebrand disease is the underlying cause for meborrhagia in a small but significant proportion of women. This study revealed that 6% of women with menorrhagia had Von Willebrand disease.

Von Willebrand disease type Vicenza: In search of a classification for the archetype of reduced von Willebrand factor survival.

Type Vicenza von Willebrand disease (VWD) features a von Willebrand factor (VWF) with a very short half‐life, and is classified as a form of type 1 VWD. To test the appropriateness of type Vicenza VWD classification, the main features of 17 patients from eight unrelated families were analysed. They had low VWF antigen levels and function (always below 20 U/dl); ristocetin‐induced platelet aggregation sometimes normal, sometimes reduced/absent (even in the same patient); normal platelet VWF levels; an increased VWF propeptide to VWF antigen ratio (8.74 ± 1.65 vs. normal 1.04 ± 0.28) and a reduced VWF half‐life. Plasma VWF multimer levels were homogeneously reduced, and unusually large VWF multimers were sometimes present. Recombinant p.R1205H VWF showed a normal synthesis, release, function, and multimer pattern, with no ultra‐large VWF multimers. The mathematical model by Galvanin et al. was used to explore the kinetic changes in VWF after DDAVP. It showed that the release, but especially the proteolysis (k proteol 1.0−3 ± 2.5−3 vs. normal 4.5−4 ± 6.4−4) and elimination (k el 1.0−2 ± 5.2−3 vs. normal 1.1−3 ± 6.8−4) of type Vicenza VWF were significantly higher than normal. The increased elimination is consistent with the short half‐life, while the increased proteolysis was unexpected. As a shorter survival of VWF is wholly responsible for the type Vicenza VWD phenotype (VWF synthesis, structure and function are normal), it might be better to classify it as a type 2 VWD (rather than type 1) to emphasise the greater interaction with clearance receptors as a new VWF functional defect.

The Discordance between Offsite to Onsite Testing for Von Willebrand Disease in Post-Menarchal Females: A Multi-Center Study

The Discordance between Offsite to Onsite Testing for Von Willebrand Disease in Post-Menarchal Females: A Multi-Center Study

Identification and characterization of the elusive mutation causing the historical von Willebrand Disease type IIC Miami

Essentials Von Willebrand disease IIC Miami features high von Willebrand factor (VWF) with reduced function. We aimed to identify and characterize the elusive underlying mutation in the original family. An inframe duplication of VWF exons 9-10 was identified and characterized. The mutation causes a defect in VWF multimerization and decreased VWF clearance from the circulation. Background A variant of von Willebrand disease (VWD) type 2A, phenotype IIC (VWD2AIIC), is characterized by recessive inheritance, low von Willebrand factor antigen (VWF:Ag), lack of VWF high-molecular-weight multimers, absence of VWF proteolytic fragments and mutations in the VWF propeptide. A family with dominantly inherited VWD2AIIC but markedly elevated VWF:Ag of > 2 U L(-1) was described as VWD type IIC Miami (VWD2AIIC-Miami) in 1993; however, the molecular defect remained elusive. Objectives To identify the molecular mechanism underlying the phenotype of the original VWD2AIIC-Miami. Patients and Methods We studied the original family with VWD2AIIC-Miami phenotypically and by genotyping. The identified mutation was recombinantly expressed and characterized by standard techniques, confocal imaging and in a mouse model, respectively. Results By Multiplex ligation-dependent probe amplification we identified an in-frame duplication of VWF exons 9-10 (c.998_1156dup; p.Glu333_385dup) in all patients. Recombinant mutant (rm)VWF only presented as a dimer. Co-expressed with wild-type VWF, the multimer pattern was indistinguishable from patients' plasma VWF. Immunofluorescence studies indicated retention of rmVWF in unusually large intracellular granules in the endoplasmic reticulum. ADAMTS-13 proteolysis of rmVWF under denaturing conditions was normal; however, an aberrant proteolytic fragment was apparent. A decreased ratio of VWF propeptide to VWF:Ag and a 1-desamino-8-d-arginine vasopressin (DDAVP) test in one patient indicated delayed VWF clearance, which was supported by clearance data after infusion of rmVWF into VWF(-/-) mice. Conclusion The unique phenotype of VWD2 type IIC-Miami results from dominant impairment of multimer assembly, an aberrant structure of mutant mature VWF and reduced clearance in vivo.

Von Willebrand disease biology

*Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Thrombosis and Hemostasis, C2-R Einthoven Laboratory for Experimental Vascular Medicine, LeidenUniversity Medical Center, Leiden, The Netherlands; Centre for Haematology, Imperial College London, HammersmithHospital Campus, London;§INSERM U770, Cedex, France; and –Department of Pathology and Molecular Medicine, QueensUniversity, Kingston, ON, Canada

Similarity in Joint Function Limitation in Type 3 VWD and Moderate Hemophilia A

Type 3 von Willebrand Disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) antigen, and a parallel decrease in FVIII activity and VWF function. In addition to mucocutaneous bleeding, hemarthrosis and limited joint range of motion (ROM) have been reported. We have previously shown that lower FVIII level, increasing age, history of joint bleeding, and higher body mass index (BMI) are negatively associated with joint function in the Type 3 VWD population. The goal of this study was to compare subjects with similar FVIII levels (Type 3 VWD versus moderate Hemophilia A) in order to further isolate the role of FVIII and other variables in joint ROM loss. A previously validated cohort of subjects with Type 3 VWD and FVIII ≤ 5% were compared to subjects with moderate Hemophilia A (FVIII 1–5%) within the CDC-sponsored Universal Data Collection (UDC) database, which contains information on subjects with bleeding disorders followed at Hemophilia Treatment Centers in the U.S. Subjects with a history of an inhibitor were excluded. At each visit, a joint function score was calculated for each subject as the overall proportion of normal joint ROM based on measures taken of 10 joints. Longitudinal data analysis was performed to identify factors affecting joint ROM loss over time.Clinical characteristics of the two cohorts are as follows:Moderate Hemophilia A (n=1814)Type 3 VWD (n=100)p-valueGender (F:M)17:179749:51< 0.001Age at 1st visit (mean, range)19.1 (2–69)21.9 (3–69)0.09History of bleed (%)1773 (97.7%)99 (99.0%)0.72Age of 1st bleed (mean, SD)2.5 (4.7)2.0 (5.6)0.45# joint bleeds (mean, SD)3.0 (6.9)1.6 (4.3)0.09# muscle bleeds (mean, SD)0.9 (2.5)0.4 (1.2)0.07# other bleeds (mean, SD)*1.2 (4.6)4.0 (14.5)<0.001Home Infusion (%)1056 (58.2%)53 (53.0%)0.03Prophylaxis (%)379 (20.9%)12 (12.0%)0.03FVIII level (mean, SD)**2.9 (1.3)2.6 (1.4)0.12* Includes mucosal** 4 patients with VWD did not have explicit FVIII levels and were excluded from this analysis.Longitudinal data analysis revealed no significant difference in joint ROM loss over time between the Type 3 VWD and moderate Hemophilia A cohorts. Age, non-white race, lower FVIII level, BMI, use of prophylaxis, and history of an invasive joint procedure or orthopedic appliance were significantly associated with joint ROM loss over time. In the subgroup with age < 20 years old, only increasing age, non-white race and male gender were significantly associated with increased joint ROM loss. A predictive model confirmed the significance of a lower FVIII level as a risk factor for the development of increased joint ROM loss over time. A lower FVIII value was found to significantly contribute to both joint and muscle bleeding, but not other (including mucosal) bleeding in the combined cohort. In conclusion, subjects with Type 3 VWD and moderate Hemophilia A both demonstrate a strong bleeding phenotype, with bleeding symptoms beginning at a young age and frequently requiring home therapy. In addition to reporting similar numbers of joint bleeds, subjects with Type 3 VWD and FVIII ≤ 5% have a similar rate of joint ROM loss over time compared to subjects with moderate Hemophilia A. Both longitudinal data analysis and predictive modeling demonstrate that a lower FVIII level significantly contributes to increased joint ROM loss over time. These results help confirm the similarity of the joint bleeding phenotype between subjects with Type 3 VWD and moderate hemophilia A and support that the FVIII level plays an important role in the loss of joint ROM over time in patients with Type 3 VWD. As the ROM loss over time in the two groups was indistinguishable, and patients with hemophilia are known to have normal VWF levels, it suggests that a low VWF antigen may not contribute any additional risk to joint function limitation in the Type 3 VWD population. Further studies are warranted to further define risk factors for joint function limitation in the Type 3 VWD population in order to identify a subgroup that may benefit from prophylactic therapy.

The Clinical Utility of the 1-Deamino-8-D-Arginine Vasopressin (DDAVP) Trial in the Management of Patients with Von Willebrand Disease: A Retrospective Study.

DDAVP has been shown to be effective in securing hemostasis in certain patients with mild and moderate von Willebrand disease (vWD) undergoing hemostatic challenge. However as the response to this agent is heterogeneous, it is currently recommended that patients with vWD undergo a therapeutic trial of this agent prior to any elective invasive procedures. We performed a retrospective review of DDAVP response in patients with vWD in order to determine which patient groups most benefit from a DDAVP trial, and the optimum testing protocol, particularly examining the need to recall the patient for testing at 24 hours.Between 1990–2006 we identified 129 patients undergoing DDAVP trial for a historical diagnosis of vWD based on a previous low von Willebrand factor antigen (vWF:Ag), ristocetin cofactor activity (vWF:RiCoF) or collagen-binding activity (vWF:CBA), and a bleeding history. Twenty-one patients were excluded from analysis having normal vWD parameters prior to DDAVP infusion. The median age of patients was 25 years, (range 4–64), with 60% being female. The distribution of vWD subtypes was as follows: 94 type 1, eight type 2A, and six with a bleeding phenotype and no abnormality other than mildly reduced vWF:RiCoF. DDAVP was administered by IV infusion with samples taken for testing pre-infusion and between 1–2 hours post infusion. Additional testing at 24 hours was performed in the majority after 2003. A complete response (CR) was defined as an increase in all vWD parameters to within the normal range (vWF:Ag [50–200%], vWF:RiCoF [50–150%], vWF:CBA [50–200%]); a partial response (PR), an increase to between 30% and lower limit of normal.Results: In the type 1 vWD cohort, at one hour post infusion 75/94 experienced CR, 15/94 PR and 4/94 no response (NR). All patients with baseline vWF:Ag >15% and vWF:CBA >9% responded. Virtually all patients with a baseline vWF:Ag >25%, vWF:RiCoF >25% and a vWF:CBA >27% had a CR at one hour. Factor VIII levels reached normal levels in all cases regardless of vWF responses. No patient with type 2A responded, and all patients with mildly reduced RiCoF in isolation achieved CR. Nineteen patients with type 1 disease underwent testing at 24 hours. 13/15 with type 1 and a CR at one hour had adequate (>30%) levels at 24 hours. None of four patients with a PR at one hour had adequate levels at 24 hours. Median vWF:Ag and vWF:CBA levels were approximately 20% above initial levels at 24 hours in the responders.Conclusions: Patients with type 2A, and type 1 vWD with baseline vWF:Ag ≤15% and vWF:CBA ≤9% should not undergo DDAVP trial as they are unlikely to respond. Patients with type 1 vWD and baseline vWF:Ag >25%, vWF:RiCoF >25% and vWF:CBA >27%, or others with isolated low vWF:RiCoF and bleeding phenotype, need not undergo a DDAVP trial to establish efficacy. However, these patients may still require a DDAVP trial for assessment of safety and tolerability. It is not essential to measure factor VIII levels in patients who are undergoing a DDAVP trial. All patients with vWD parameters in the normal range one hour following DDAVP should be considered for further testing at 24 hours to identify the occasional suboptimal responder. Implementation of this testing strategy would reduce the requirement for DDAVP trials by approximately 35%, based upon our series.

Atypical variant of acquired von Willebrand syndrome in Wilms tumor: is hyaluronic acid secreted by nephroblastoma cells the cause?

Acquired von Willebrand syndrome (AvWS) has been reported in eight children with Wilms tumor (nephroblastoma in four boys and four girls) at a mean age of 3.3 years (range, 0.33-9 years). Only three of eight patients with AvWS in Wilms tumor presented with mild mucocutaneous bleeding symptoms. The AvWS in seven children with Wilms tumor featured either undetectable or very low von Willebrand factor antigen (vWF.Ag) levels (mean, 3%) and decreased values for vWF ristocetin cofactor (RCF) activity (mean, 20%) and factor VIII coagulant (VIIIc) activity (mean, 16%). The response to 1-desamino-8-arginine vasopressin (DDAVP) was good in two and poor in one patient. Multimeric analysis of the vWF showed a normal pattern of type I von Willebrand disease (vWD) in three patients and an absence of multimers consistent with type III vWD in two patients. The higher functional levels, as compared with antigen levels, with increased ratios for factor VIIIc/vWFAg (mean, 5.3) and vWF.RCF/vWF.Ag (mean, 6.6) in seven patients with Wilms tumor are unexplained physiologically and are not consistent with type I vWF deficiency. The absence of vWD in the patient's family, and the return of factor VIII-vWF parameters to normal after chemotherapy or surgical removal of the Wilms tumor, support the diagnosis of AvWS causally related to the Wilms tumor. The causative agent is thought to be hyaluronic acid secreted by nephroblastoma cells of the Wilms tumor. Prospective studies to determine the nature of AvWS in children with Wilms tumor are warranted.

The semi-quantitative assessment of menstrual flow in relation to clinical and hematological parameters

The hemostasis of menstruation has not been extensively studied particularly since the development of laboratory tests for von Willebrand factor, a glycoprotein that plays a critical role platelet aggregation. Objective: To determine the relationship of menstrual flow to clinical and hematological parameters. Methods: We studied 155 (56 blood type O/99 blood type non-O) normal female volunteers that met the following criteria: age 12–50; not taking an oral contraceptive, estrogen, or Coumadin; not pregnant; regular periods. A questionnaire was administered regarding the patient’s medical history. A pictorial chart score of menstrual blood flow was obtained using standard tampons/pads for all participants; this semi-objective measure has previously been validated to be diagnostic of menorrhagia at a score of >185. Menstrual coagulation sampling was within the first 3 days of the cycle. We then analyzed by multiple linear regression analysis the pictorial chart score assuming a log-normal distribution as a dependent variable with the following clinical and laboratory parameters as independent variables. Results: The mean age was 35.7 ± 7.4 years. The mean pictorial chart score was 119.1 ± 76.3. ∗ Independent Variable With Pictorial Chart Score as Dependent Variable Parameter Estimate (slope) P Value (two-sided) Age 0.007 .2 Number of prior births 0.16 .02 Blood group type −0.06 .3 Hematocrit −0.01 .3 Factor VIII activity 0.002 .1 von Willebrand factor activity (ristocetin cofactor) 0.001 .3 von Willebrand factor antigen −.003 0.04 ∗ ∗ P value is one-sided (an inverse association was hypothesized). Conclusion: A history of prior births and laboratory evidence of a low von Willebrand factor antigen appear to predict for increased menstrual flow; studies are ongoing in applying these parameters in women presenting with menorrhagia.

Synergistic effect of storage pool deficient platelets and low plasma von willebrand factor on the severity of the hemorrhagic diathesis in hermansky‐pudlak syndrome

A study of 565 Puerto Rican patients with storage pool deficient (SPD) Hermansky-Pudlak syndrome (HPS) demonstrated that most HPS patients had minor bleeding episodes while others had repeated, severe hemorrhagic episodes requiring transfusion. The severity of bleeding in these latter patients could not be attributed to their SPD alone. As swine with SPD platelets and low von Willebrand factor antigen (vWF:Ag) have more severe hemorrhages than pigs with either defect alone, 146 albino patients and 46 normally pigmented patients were examined for their level of vWF:Ag. The risk of SPD HPS patients having severe, repeated bleeding episodes increased when vWF:Ag fell below 70 U/dL. Family studies indicated that low vWF:Ag levels were more frequently associated with O blood group than from a gene suppressing production or release of vWF1. HPS patients should be tested for vWF:Ag levels.