von Willebrand disease.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The disorder is characterized by excessive mucocutaneous bleeding. The most common bleeding manifestations of this condition include nosebleeds, bruising, bleeding from minor wounds, menorrhagia or postpartum bleeding in women as well as bleeding after surgery. Other less frequent symptoms include gastrointestinal bleeding, haematomas or haemarthroses. VWD pathophysiology is complex and results from defects in von Willebrand factor (VWF) glycoprotein. Quantitative deficiencies are responsible for type 1 VWD with a partial decrease of VWF and type 3 with the complete absence of VWF. Qualitative abnormalities cause type 2 VWD, being further divided into types 2A, 2B, 2M and 2N. Although common, VWD is at risk of misdiagnosis, overdiagnosis and underdiagnosis owing to several factors, including complex diagnosis, variability of bleeding symptoms, presence of external variables (blood groups and other physiological modifiers such as exercise, thyroid hormones, oestrogens, and ageing), and lack of disease awareness among non-specialist health-care providers. Establishing the correct VWD diagnosis requires an array of specialized phenotypic assays and/or molecular genetic testing of the VWF gene. The management of bleeding includes increasing endogenous VWF levels with desmopressin or infusion of exogenous VWF concentrates (plasma-derived or recombinant). Fibrinolytic inhibitors, topical haemostatic agents and hormonal therapies are used as effective adjunctive measures.

Low von Willebrand Factor in Children and Adolescents: A Review.

Importance: Recent studies have documented increased bleeding symptoms and related complications in patients with low von Willebrand factor (VWF), highlighting the clinical significance of this entity. Because children and adolescents with VWF deficiencies often present to primary care physicians with bleeding symptoms, physicians need to be aware of this condition for early detection. Observations: Studies have found that children and adolescents with low VWF (VWF levels of 30-50 IU/dL) can present with clinically significant bleeding, including mucosal, menstrual, postsurgical, and posttraumatic bleeding, leading to complications such as anemia, iron deficiency, transfusion, hospitalization, and poor quality of life. Detecting and promptly managing low VWF in children and adolescents with bleeding are essential because failure to do so can lead to significant morbidity in adulthood, especially among female patients, including continued heavy menstrual bleeding; postpartum hemorrhage; related gynecologic complications, such as hemorrhagic ovarian cysts; and surgical interventions for heavy menstrual bleeding, including hysterectomy. This narrative review summarizes the observations of several studies that have shed light on the pathophysiologic mechanisms of low VWF and bleeding in these patients and the available diagnostic modalities and treatment options. Conclusions and Relevance: Studies in children and adolescents have provided important insights into the clinical phenotype, complications, pathophysiologic mechanisms, evaluation, and management of low VWF, now recognized as an important clinicopathologic entity, as presented in this review. As gatekeepers, primary care physicians play an important role in guiding patients with this recently recognized clinicopathologic entity toward appropriate specialty care and providing continued comanagement to prevent future complications as the patients enter adulthood.

Endothelial Function in Patients With Von Willebrand Disease.

In patients with von Willebrand disease (vWD) the interest in age-related comorbidities has grown, because the life expectancy of these patients has increased. The research question of this study was whether patients with vWD show a different endothelial function compared to the general population. A total of 37 patients with type 1 (n = 23), type 2 (n = 10) and type 3 (n = 4) vWD, 14 controls and 38 patients with coronary artery disease (CAD) were included in this study. Five markers of endothelial dysfunction (MOED) were determined. Moreover, the endothelial function was examined using the Itamar Endo-PAT. The reactive hyperemia index (RHI) was calculated from the results. The markers soluble intercellular adhesion molecule-1 (p = 0.171), P-Selectin (p = 0.512), interleukin-6 (p = 0.734) and monocyte chemoattractant protein-1 (p = 0.761) showed higher levels in patients with vWD, but were not significantly different compared to the control group. RHI was impaired in CAD-patients (1.855), whereas vWD patients had mean results of 1.870 and controls 2.112 (p = 0.367). In this study, the endothelial function measurements of patients with von Willebrand disease were not significantly different compared to healthy controls.

Peripartum management of a parturient with type 1C (clearance) von Willebrand disease.

Peripartum replacement of factor VIII and von Willebrand factor is not usually required in type 1 von Willebrand disease, as the levels of endogenous factors tend to increase to within the normal range as a physiological change of pregnancy. However, there is wide heterogeneity of genotypes and phenotypes associated with type 1 von Willebrand disease. Here, we describe the anesthetic management of a parturient with type 1C von Willebrand disease, a subtype characterized by decreased plasma von Willebrand factor survival.

Decreased RPM reduces von Willebrand factor degradation with the EVAHEART LVAS: implications for device-specific LVAD management.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) produces supraphysiologic shear stress that causes von Willebrand factor (VWF) degradation and a bleeding diathesis. Reduction of revolutions per minute (RPM) with axial-flow LVADs does not decrease shear stress enough to reduce VWF degradation and bleeding. However, it is unknown if RPM reduction with centrifugal flow LVADs may minimize VWF degradation. We tested the hypothesis that RPM reduction preserves VWF multimers in the centrifugal-flow EVAHEART left ventricular assist system (LVAS), which is designed to minimize shear stress and blood trauma. METHODS: Whole blood samples were collected from humans (n = 28). Blood was circulated in ex vivo mock circulatory loops for 6 hours with an EVAHEART LVAS at 2300 (n = 12), 2100 (n = 8), or 1800 RPM (n = 8). Immunoblotting was used to resolve and quantify VWF multimers and degradation fragments. RESULTS: RPM reduction from 2300 to 2100 to 1800 RPM significantly decreased EVAHEART blood flow from 5.8 ± 0.4 to 4.3 ± 0.6 to 4.1 ± 0.5 L/min (analysis of variance [ANOVA], P = .03). RPM reduction protected VWF from pathologic degradation. At lower RPMs, significantly greater levels of VWF multimers were observed (ANOVA, P = .001). Similarly, at lower RPMs, significantly fewer VWF fragments, a product of VWF degradation, were observed (ANOVA, P = .007). CONCLUSIONS: RPM reduction significantly reduced VWF degradation with the centrifugal-flow EVAHEART LVAS, an LVAD specifically designed with low shear stress. Different LVADs have unique hematologic footprints and should be managed with device-specific protocols. Adjustment of RPM to minimize blood trauma while still maintaining physiologic hemodynamics has the potential to decrease complications related to LVAD-associated von Willebrand's disease, such as gastrointestinal bleeding and hemorrhagic stroke.

Phenotypic and Genotypic Characterization of von Willebrand Factor Gene (Exon 18 and 20) in Saudi Healthy Individuals.

INTRODUCTION: Von Willebrand disease (VWD) is an autosomal congenital bleeding syndrome that was described as being the most widespread genetic condition among men. In Saudi Arabia, the genotyping of the VWF gene is necessary to establish a diagnosis procedure for VWD. AIM: The current research, however, attempted to evaluate the phenotypic-genotypic association of the Von Willebrand factor (exon 18 and 20) gene in healthy subjects to establish effective molecular diagnostic strategies. METHODS: This was a cross-sectional retrospective included 100 healthy people who have been chosen from King Fahad University Hospital. Whole blood samples were collected from all individuals, as well as the laboratory analysis was done using automatic analyzers for; platelet count, ABO blood group and coagulation parameters. DNA Sanger sequencing has been used to sequestrate the full exons 18 and 20. RESULTS: In exon 18 of healthy people, three unusual sequence variations (1 missense and 2 synonymous; rs775479826, rs1286572448 and rs369828268) compared to other recorded VWF variations (3 missense and 1 synonymous; c.2365A > G, c.2385T > C, c.2344C > T and c.2340C > G). But in exon 20 only 1 synonymous novel (rs113240752) 1 registered VWF variations in missense (c.2555G > A) were identified. CONCLUSION: The present variants found on those participates could be a realistic approach to detect mutation in the VWF gene to illustrating the relationship of phenotypic and genetic abnormalities variables may lead to determining the functional effect in mutations specific to the Saudi people that can be used to develop a diagnostic tool for VWD in KSA.

Thrombin generation during a regular menstrual cycle in women with von Willebrand disease.

Fluctuations of the sex steroids during the menstrual cycle might significantly influence hemostasis. This association, derived from a number of the observations on healthy women, is yet to be described in females affected by bleeding disorders. The aim of the current study was to assess the changes in hemostatic variables in women with vWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with healthy controls. The study group included 12 vWD-affected females with regular menstrual cycle, with none of them being prescribed any hormonal treatment. The control group consisted of 102 healthy females, matched for age and BMI. Within the vWD group FVIII and FX were both significantly higher during follicular phase than in luteal phase (p = 0.013 and p = 0.033 respectively). AT, FII, FVII and FX were higher in women with vWD, compared with controls during both phases of the menstrual cycle (p < 0.0005, p < 0.0005, p = 0.001 and p < 0.0005). In women with vWD, lag time and time to peak were prolonged during both phases of the menstrual cycle(p < 0.0005), while peak thrombin concentration was reduced (p = 0.003 and p = 0.002 during follicular and luteal phase respectively) compared to healthy peers. Lower levels of FVIII and FX during luteal phase may predispose women to the development of the menorrhagia - common complication of vWD. Women with vWD need more time to reach the peak thrombin concentration, while the latter still remains less than in healthy women. Higher levels of AT in vWD-affected females, compared to controls, may also contribute to the existing bleeding tendency in this cohort.

Clinical features of children, adolescents, and adults with coexisting hypermobility syndromes and von Willebrand disease.

We present five patients with coexistent von Willebrand disease (VWD) and Ehlers-Danlos syndrome and 21 with VWD and joint hypermobility. Females outnumbered males ten to three, Beighton scores were documented in 58% (15 of 26 patients), and several patients experienced moderately severe bleeding. We believe coexistent hypermobility disorder with VWD potentially affects bleeding severity and want to raise awareness among hematologists. Evaluation by geneticists is recommended because of the varying complexities observed across the disease spectrum, and the availability of new genetic tests should lead to more accurate diagnoses for the various hypermobility disorders.

Hemostasis and Thrombosis in the Oldest Old.

There is a growing proportion of the elderly population in the Western world, and these individuals require special considerations regarding a broad variety of aspects, including treatment approaches to illnesses that affect all age groups. The hemostatic system in individuals changes considerably with aging. Specifically, changes in levels of procoagulant and natural anticoagulant factors along with thrombopathy simultaneously create a hypercoagulable state and hemostatic difficulties. Underlying morbidities, such as congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and cancer, increase the risk for venous and arterial thrombosis. This population is also increasingly affected by acquired bleeding disorders, including acquired hemophilia and acquired von Willebrand syndrome, as well as mild congenital bleeding disorders. Real-life data demonstrate that recurrent and fatal venous thromboembolism is the major hemostatic concern in the elderly. The fact that treatment of thrombotic complications increases the bleeding risk also has to be taken into consideration, particularly in the older age group. This remains true in the era of direct oral anticoagulants. In conclusion, maintaining a delicate balance between thrombosis and bleeding risks is the key issue in providing qualified treatment to elderly patients.

Prevalence and Risk Factors Associated With Hypertension in von Willebrand Disease.

BACKGROUND: von Willebrand factor (VWF) is a biomarker for endothelial damage. Increased VWF levels are observed in hypertension (HTN) and disorders of endothelial dysfunction, for example, atherosclerotic heart disease (ASHD) and diabetes. Whether low VWF protects against HTN is unknown. METHODS: To determine prevalence and risk factors for HTN in patients with von Willebrand disease (VWD), we conducted a cross-sectional analysis of discharge data from the National Inpatient Sample, 2009 to 2011. Group comparisons were performed by Rao-Scott χ2 test. Odds of HTN and HTN outcomes in VWD were estimated by weighted multivariable logistic regression. RESULTS: The prevalence of hypertension in patients with VWD (N = 7556), 37.35%, was significantly lower than that in non-VWD patients (N = 19 918 970), 49.40%, P < .0001. Hypertension risk factors (hyperlipidemia, diabetes, smoking, hepatitis C, and HIV) and HTN outcomes (ASHD, myocardial infarction [MI], ischemic stroke, and renal failure) were less common in patients with VWD than in non-VWD patients, all P ≤ .0001. Patients with VWD were younger, 49.67 versus 57.30 years, Caucasian, 82.23% versus 68.35%, and female, 75.44% versus 59.61%, P < .0001. Patients with HTN were older, 67.55 versus 47.29 years, male, 45.99% versus 34.90%, and had more HTN risk factors and HTN outcomes than those without HTN, all P < .0001, including male and female subgroups, each P < .0001. The unadjusted odds of HTN in patients with VWD (odds ratio [OR] = 0.611, P < .0001) and of HTN outcomes in patients with VWD (ASHD, OR = 0.509; MI, OR = 0.422; ischemic stroke, OR = 0.521; renal failure, OR = 0.420, all P < .0001) became insignificant after adjustment for HTN risk factors plus demographics (age/race/gender), OR = 1.035, P = .260. CONCLUSION: The risk of HTN is reduced in patients with VWD, but not after adjustment for HTN risk factors plus demographics, as patients with VWD not having HTN are also typically young, Caucasian, and female.

Patient, caregiver, and provider perceptions of pain and pain management in adolescents and young adults with bleeding disorders.

INTRODUCTION: Recurrent bleeding and associated pain are critical components in the management of bleeding disorders, yet scant data describe perceptions of pain in this patient population. OBJECTIVE: This study assessed perceptions of pain and pain management in adolescents and young adults (AYAs) with haemophilia or von Willebrand disease (VWD) to determine agreement/disagreement between patients, caregivers and health care providers. METHODS: Using an online questionnaire, AYA patients (N=89), their caregivers (N=77), and providers (N=54) reported on pain perception, pain treatment and pain control. Acute and chronic pain was measured in patients via the Faces Pain Scale-Revised (FPS-R). Questionnaires queried about pharmacologic and non-pharmacologic pain management methods and how well providers and caregivers helped to manage pain. RESULTS: Poor agreement existed between patients and caregivers across all pain levels, perception of pain control and effectiveness of pain management. Specifically for chronic pain, poor agreement was noted between patients and caregivers (kappa=0.04; 29% agreement) and patients and providers (kappa=-0.07; 21.4% agreement). Among patients reporting acute or chronic pain, only 67% and 43%, respectively, utilized medication for their specific pain. Patients used more opioid medications than expected by their providers. On average, AYAs reported initial use of pain medications for chronic pain at 11.5 years. CONCLUSIONS: Ongoing research is needed in haemophilia and VWD pain management, and on the differences in pain perception between patients, caregivers and providers. As chronic pain often begins at an early age, optimal pain management should include acknowledging patient complaints, exploring pharmacologic and non-pharmacologic options, and optimizing prophylaxis.

von Willebrand factor deficiency leads to impaired blood flow recovery after ischaemia in mice.

Neovascularisation, i. e. arteriogenesis and angiogenesis, is an inflammatory process. Therefore attraction and extravasation of leukocytes is essential for effective blood flow recovery after ischaemia. Previous studies have shown that von Willebrand factor (VWF) is a negative regulator of angiogenesis. However, it has also been shown that VWF facilitates leukocyte attraction and extravasation. We aimed to investigate the role of VWF in arteriogenesis and angiogenesis during post-ischaemic neovascularisation. Wild-type (WT) and VWF deficient (VWF-/-) C57BL/6 mice were subjected to hindlimb ischaemia via double ligation of the left femoral artery, and blood flow recovery was followed over time, using Laser Doppler Perfusion Imaging. Blood flow recovery was impaired in VWF-/- mice. After 10 days, VWF-/- mice showed a 43 ± 5 % recovery versus 68 ± 5 % in WT. Immunohistochemistry revealed that both arteriogenesis in the adductor muscles and angiogenesis in the gastrocnemius muscles were reduced in VWF-/- mice. Furthermore, leukocyte infiltration in the affected adductor muscles was reduced in VWF-/- mice. Residual paw perfusion directly after artery ligation was also reduced in VWF-/- mice, indicating a decrease in pre-existing collateral arteriole density. When we quantified collateral arterioles, we observed a 31 % decrease in the average number of collateral arterioles in the pia mater compared to WT mice (57 ± 3 in WT vs 40 ± 4 pial collaterals in VWF-/-). We conclude that VWF facilitates blood flow recovery in mice. VWF deficiency hampers both arteriogenesis and angiogenesis in a hindlimb ischaemia model. This is associated with impaired leukocytes recruitment and decreased pre-existing collateral density in the absence of VWF.

Perioperative onset of acquired von Willebrand syndrome: Comparison between HVAD, HeartMate II and on-pump coronary bypass surgery.

OBJECTIVES: Acquired von Willebrand syndrome (AvWS) is associated with postoperative bleeding complications in patients with continuous flow left ventricular assist devices (CF-LVADs). The aim of this study is to analyze the perioperative vWF profile comparing an axial pump (HMII) to a centrifugal pump (HVAD) regarding the correlation between perioperative occurrence of AvWS, early- and late-postoperative bleeding events. METHODS: From July 2013 until March 2015 blood samples of 33 patients (12 HMII/ 8 HVAD/ 13 controls) were prospectively collected at 12 different time points and analyzed for the vWF antigen (vWF:Ag), its activity (vWF:Ac) and the vWF:Ac/vWF:Ag-ratio (vWF:ratio). The follow up period for postoperative bleeding events was from July 2013 until July 2016. RESULTS: Postoperatively, there was no difference in the vWF-profile between HVAD and HMII groups. However, a subgroup of patients already had significantly lower vWF:ratios preoperatively. Postoperatively, both CF-LVAD groups presented significantly lower vWF:ratios compared to the control group. Bleeding events per patient-year did not differ between the two groups (HMII vs. HVAD: 0.67 vs. 0.85, p = 0.685). We detected a correlation between vWF:ratio <0.7at LVAD-start (r = -0.583, p = 0.006) or at the end of surgery (r = -0.461, p = 0.035) and the occurrence of pericardial tamponade. In the control group, the drop in both vWF:Ag and vWF:Ac recovered immediately postoperatively above preoperative values. CONCLUSION: A subgroup of patients with end-stage heart failure already suffers AvWS preoperatively. In both CF-LVAD groups, AvWS begins immediately after surgery. Intraoperative vWF:ratios <0.7 correlate with higher incidences of pericardial tamponade and re-operation. The presumably dilutive effect of the heart lung machine on vWF vanishes immediately at the end of surgery, possibly as part of an acute-phase response.

von Willebrand Disease: A Concise Review and Update for the Practicing Physician.

von Willebrand disease (vWD) is the most common inherited disorder of hemostasis and comprises a spectrum of heterogeneous subtypes. Significant advances have been made in understanding von Willebrand factor ( vWF) gene mutations, resultant physiologic deficits in the vWF peptide, and their correlation to clinical presentation. Diagnostic tests for this disorder are complex, and interpretation requires a thorough understanding of the underlying pathophysiology by the practicing physician. The objective of this review is to summarize our current understanding of pathophysiology, laboratory investigations, and evolving treatment paradigm of vWD with the availability of recombinant von Willebrand factor.

Angiogenic characteristics of blood outgrowth endothelial cells from patients with von Willebrand disease.

BACKGROUND: Endothelial von Willebrand factor (VWF) inhibits angiogenesis. Accordingly, blood outgrowth endothelial cells (BOECs) isolated from von Willebrand disease (VWD) patients showed enhanced in vitro angiogenesis when compared with healthy control BOECs. Characterization of the angiogenic response of VWD BOECs is limited and differences between the different types of VWD have not been investigated in detail. OBJECTIVES: The aim of this study was to further explore the potential pathogenic effect of VWF mutations on angiogenesis. METHODS: BOECs were isolated from four healthy individuals, 10 patients with VWD and one heterozygous carrier of a type 2N mutation. Cell migration and tube formation were measured. RESULTS: Migration velocity and total tube formation were similar between VWD patients and controls in general. BOECs from the type 3 VWD patient and one type 2B patient showed increased migratory velocity and tube formation compared with BOECs from other patients and healthy controls. Directional migration was impaired in eight out of 10 VWD BOECs and the ability to form tubes was limited to early passage numbers, but not for BOECs from healthy controls. CONCLUSION: BOECs can be a useful tool for ex vivo assessment of endothelial cell function in patients with different types of VWD, but possible limitations, such as early loss of angiogenic capacity, should be recognized. BOECs from most VWD patients consistently showed impairment in the directionality of migration. This is the first report on angiogenic properties of a type 3 VWD BOEC, which showed increased in vitro angiogenesis.

Menstrual Patterns and Treatment of Heavy Menstrual Bleeding in Adolescents with Bleeding Disorders.

STUDY OBJECTIVE: To characterize menstrual bleeding patterns and treatment of heavy menstrual bleeding in adolescents with bleeding disorders. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of female patients aged nine to 21 years with known bleeding disorders who attended a pediatric gynecology, hematology, and comprehensive hematology/gynecology clinic at a children's hospital in a metropolitan area. MAIN OUTCOME MEASURES: Prevalence of heavy menstrual bleeding at menarche, prolonged menses, and irregular menses among girls with bleeding disorders and patterns of initial and subsequent treatment for heavy menstrual bleeding in girls with bleeding disorders. RESULTS: Of 115 participants aged nine to 21 years with known bleeding disorders, 102 were included in the final analysis. Of the 69 postmenarcheal girls, almost half (32/69, 46.4%) noted heavy menstrual bleeding at menarche. Girls with von Willebrand disease were more likely to have menses lasting longer than seven days. Only 28% of girls had discussed a treatment plan for heavy menstrual bleeding before menarche. Hormonal therapy was most commonly used as initial treatment of heavy menstrual bleeding. Half (53%) of the girls failed initial treatment. Combination (hormonal and non-hormonal therapy) was more frequently used for subsequent treatment. CONCLUSIONS: Adolescents with bleeding disorders are at risk of heavy bleeding at and after menarche. Consultation with a pediatric gynecologist and/or hematologist prior to menarche may be helpful to outline abnormal patterns of menstrual bleeding and to discuss options of treatment in the event of heavy menstrual bleeding.

Comparison of several von Willebrand factor (VWF) activity assays for monitoring patients undergoing treatment with VWF/FVIII concentrates: improved performance with a new modified automated method.

BACKGROUND: The ability of von Willebrand factor (VWF) to bind platelet GP Ib and promote platelet plug formation is measured in vitro using the ristocetin cofactor (VWF:RCo) assay. Automated assay systems make testing more accessible for diagnosis, but do not necessarily improve sensitivity and accuracy. OBJECTIVE: We assessed the performance of a modified automated VWF:RCo assay protocol for the Behring Coagulation System (BCS(®) ) compared to other available assay methods. METHODS: Results from different VWF:RCo assays in a number of specialized commercial and research testing laboratories were compared using plasma samples with varying VWF:RCo activities (0-1.2 IU mL(-1) ). Samples were prepared by mixing VWF concentrate or plasma standard into VWF-depleted plasma. Commercially available lyophilized standard human plasma was also studied. Emphasis was put on the low measuring range. VWF:RCo accuracy was calculated based on the expected values, whereas precision was obtained from repeated measurements. RESULTS: In the physiological concentration range, most of the automated tests resulted in acceptable accuracy, with varying reproducibility dependent on the method. However, several assays were inaccurate in the low measuring range. Only the modified BCS protocol showed acceptable accuracy over the entire measuring range with improved reproducibility. CONCLUSIONS: A modified BCS(®) VWF:RCo method can improve sensitivity and thus enhances the measuring range. Furthermore, the modified BCS(®) assay displayed good precision. This study indicates that the specific modifications - namely the combination of increased ristocetin concentration, reduced platelet content, VWF-depleted plasma as on-board diluent and a two-curve calculation mode - reduces the issues seen with current VWF:RCo activity assays.