Von Willebrand Factor Values Research Articles

Pre-surgical level of von Willebrand factor as an evident indicator of breast cancer recurrence.

Endothelial and platelet activation as well as a disruption of haemostatic balance are crucial in cancer-dependent venous thromboembolism development. The aim of this study was to investigate the influence of von Willebrand factor (VWF), sE-selectin, sP-selectin as well as VWF/sE-selectin and sP-selectin/sE-selectin ratios on the probability of disease relapse in invasive breast carcinoma (IBrC) cases. Eighty-four patients with IA-IIB stage of IBrC who passed a comprehensive clinicopathologic evaluation were included in the study. Follow-up was completed in all patients with a 15.48 % recurrence rate. An immunoassay of VWF antigen, sE-selectin, sP-selectin, as well as an immunohistochemistry of oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was performed in all cases. The VWF/sE-selectin ratio was significantly higher in patients with poorly differentiated tumours than in those with high-differentiated tumours. A positive correlation between VWF concentration and tumour grade was noted. Eleven of 13 events happened in patients with VWF value below 600 mU/mL with recurrence rate of 25%, but only two events occurred in subject with VWF values above the 600 mU/mL (5%; P= 0.0028). Our study show that VWF could be considered as a suitable biomarker of breast cancer relapse.

Von Willebrand factor propeptide (VWFpp) — potential biomarker in inherited von Willebrand disease and acquired von Willebrand syndrome

Von Willebrand factor propeptide (VWFpp) is a fragment of a new synthesized VWF molecule that plays an important part in the biosynthesis of this protein. After completion of multimerisation of von Willebrand factor (VWF) dimers in the Golgi apparatus, as result of furin proteolysis VWFpp is truncated/disconnected from the mature VWF molecule to form a non-covalent complex with VWF. The VWFpp-VWF complex is stored in endothelial and platelet storage granules and released into the bloodstream where it dissociates into VWFpp and VWF. Plasma VWFpp level and ratio of plasma VWF propeptide (VWFpp) to VWF antigen (VWF:Ag) i.e VWFpp /VWF:Ag ratio are important biomarkers of VWF synthesis/release/clearance. These biomarkers have distinct therapeutic utility as they help to identify patients with von Willebrand disease (VWD) in whom DDAVP (desmopressin 1-desamino-8-D-arginine vasopressin) is ineffective due to rapid VWF clearance. They also have significant diagnostic value because they help to differentiate between congenital VWD subtypes as well as between congenital VWD and acquired von Willebrand Syndrome (AVWS). The purpose of the study was to determine the VWFpp level and the VWFpp/VWF: Ag ratio in patients with VWD and AVWS and to assess the significance of these biomarkers for diagnosis and management of congenital and acquired von Willebrand disease. Our study involved 120 VWD patients; 21 with AVWS and 111 healthy controls. Study results confirm that VWFpp level and the VWFpp/VWF: Ag ratio have significant value fordiscrimination between severe type 1 VWD and type 3 VWD as well as between acquired and congenital VWD which has serious implications for therapy. The biomarkers are also useful for identification of patients in whom DDAVP treatment may prove ineffective. In type 1 VWD (< 30 IU/ml) the VWFpp/VWF: Ag ratio was elevated in 57% of patients while in the group of patients with threshold VWF values (‘Low VWF’, 30–50 IU/dL) the ratio was within normal, which may be suggestive of other underlying causes of VWF deficiency. Assays in patients with non-neutralizing anti-VWF antibodies (AVWS) have shown that the VWFpp/VWF: Ag ratio can have significant impact on monitoring therapy and assessment of remission in patients with anti VWF antibodies.

Endothelial Dysfunction, Fibrinolytic Activity, and Coagulation Activity in Patients With Atrial Fibrillation According to Type II Diabetes Mellitus Status

Recent findings in atrial fibrillation (AF) patients receiving oral anticoagulation showed that diabetes without insulin therapy has a thromboembolic risk comparable to nondiabetic patients, whereas only diabetic patients on insulin have a heightened thromboembolic risk. We explored possible pathophysiological correlates of such finding on 90 AF patients on oral anticoagulation, divided according to diabetes status (n = 30 without diabetes; n = 29 with diabetes on oral antidiabetic drugs; n = 31 with insulin-requiring diabetes). We assessed von Willebrand Factor (VWF) concentration (VWF:Ag) and activity (VWF R:Co) as measures of endothelial dysfunction; and thrombin-activatable fibrinolysis inhibitor (TAFI) and prothrombin fragment 1 + 2 (F1+2) levels as markers of fibrinolytic activity and thrombin generation. Values of VWF:Ag, VWF:RCo, and TAFI were similar in the 3 groups. Patients with diabetes requiring insulin had significantly higher levels of F1+2 (median 23.1 pg/ml [interquartile range 17.6; 33.5]) than those without diabetes (16.3 pg/ml [11.5; 22.5], p = 0.036) and diabetic patients on oral antidiabetic drugs (20.6 pg/ml [13.3; 29], p = 0.046). Thus, in AF patients receiving oral anticoagulation, those with diabetes, regardless of the diabetes type (with or without insulin therapy), and those without diabetes have comparable indices of the explored parameters of endothelial dysfunction and fibrinolytic activity. Despite anticoagulant therapy, thrombin generation is selectively higher in diabetic patients' on insulin than in those without diabetes or with diabetes on oral antidiabetic drugs, with no differences between these latter 2 conditions. Thrombin generation might thus be a predominant contributor to the excess of thromboembolic risk in AF patients on insulin-requiring diabetes.

Prognostic value of von Willebrand factor for patients with atrial fibrillation: a meta-analysis of prospective cohort studies

BackgroundIt is unknown whether an abnormal level of von Willebrand factor (vWF) is correlated with the prognosis of patients with atrial fibrillation (AF) and current findings are controversial. This meta-analysis...

Utility of repeat testing in the evaluation for von Willebrand disease in pediatric patients

BackgroundVon Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by quantitative and qualitative defects in von Willebrand factor (VWF). The laboratory diagnosis of VWD in pediatric patients is complicated by VWF interassay and intra‐assay variability, stress‐induced elevations in VWF levels, and a lack of significant bleeding history with which to correlate test results. ObjectiveGuidelines recommend repeat testing in patients with a high suspicion of VWD and unclear laboratory assay results; however, no studies have evaluated the utility of repeat VWF testing in pediatric patients. MethodsThis retrospective single‐center cohort study aimed to determine clinical variables associated with requiring more than one test to diagnose VWD and to establish a cutoff VWF value above which further testing is not informative. ResultsOf 811 patients evaluated for a suspected bleeding disorder, 22.2% were diagnosed with VWD, with ~70% diagnosed on the first test. Patients with VWD were younger (5.8 vs. 8.5 years, P = .002) and more likely to have a family history of VWD (38% vs. 22%, P < .001) than those without VWD. Univariate analysis failed to identify any clinical variables that correlated with needing multiple tests for a VWD diagnosis. A cutoff of 100 IU/dL for VWF antigen or activity on the first test yielded negative predictive values >95%. ConclusionsWe demonstrate that the majority of pediatric patients had diagnostic VWF values on the first set of testing. Pediatric patients without a family history of VWD and VWF levels >100 IU/dL may not need further testing to rule out the diagnosis of VWD.

Increasing plasma ADAMTS13 activity is associated with HBeAg seroconversion in chronic hepatitis B patients during 5 years of entecavir treatment

The relationship between hemostatic system and HBeAg seroconversion (SC) of chronic hepatitis B (CHB) patients is ill-defined. We therefore evaluate the predictive value of plasma ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin motif repeats 13) and VWF (von Willebrand factor) for CHB patients during 5-year entecavir (ETV) treatment. One hundred and fourteen HBeAg positive CHB patients on continuous ETV treatment were recruited. Liver biopsies were evaluated using the METAVIR scoring system, and plasma ADAMTS13 activity (ADAMTS13: AC) and VWF antigen (VWF: Ag) were determined at baseline, 3, 12, 24, 36, and 60 months, respectively. ETV treatment resulted in an increased ADAMTS13: AC and decreased VWF: Ag (both P < 0.001) in CHB patients. Cox multivariate analysis demonstrated that the change of ADAMTS13: AC after 1-year ETV treatment was an independent predictor for HBeAg SC at year 5. The area under the receiver operating characteristic (ROC) curve for the change of ADAMTS13: AC after 1-year ETV treatment plus baseline HBV DNA was 0.873 (P < 0.001) to predict SC at year 5. The results suggested that increased ADAMTS13: AC after 1 year ETV treatment was associated with a higher seroconversion, and could be used surrogate of HBeAg SC in CHB patients during 5-year ETV treatment.

Clinical observation of desmopressin in the treatment of 15 patients with DDAVP

目的探讨去氨加压素（DDAVP）在血管性血友病（VWD）诊断和治疗中的应用价值。方法对2016年3月至2018年8月期间15例接受DDAVP治疗的VWD患者进行分析，观察治疗反应及患者用药前及用药后2 h凝血因子Ⅷ活性及血管性血友病因子（VWF）相关指标变化。结果15例VWD患者中，男7例，女8例，中位年龄23（6~46）岁。9例1型VWD患者中，7例达完全反应；1例2A型VWD患者达完全反应，5例3型VWD患者无反应。对5例患者进行VWF多聚体分析，结合其他VWF相关检测指标，DDAVP治疗效果与患者疾病分型相符合。结论DDAVP对1型VWD患者可达到较好疗效，对部分2型VWD及3型VWD患者反应不佳；VWD患者对DDAVP的治疗反应对治疗选择具有重要意义。

Cleavage and Re-Supply of von Willebrand Factor in Continuous Flow Blood Pump

Purpose Mechanical circulatory support devices are needed to enable recovery or provide a bridge to decision for patients with heart failure. The effectiveness of extending treatment duration in this therapy was previously reported to increase adverse events, such as acquired von Willebrand disease and gastrointestinal bleeding. Blood-related damage caused by medical devices is one of the most critical parameters needed to determine the performance of medical devices. For the treatment of these complications, we considered that it is very important to analyze the relationship between the cleavage of von Willebrand factor (VWF) due to shear stress and re-supply of VWF from activated platelets during blood pump circulation. We aimed to examine the alterations in the dynamics of VWF multimers in the circulating blood during VAD therapy. Methods In this study, two types (axial and centrifugal) of implantable blood pumps and a disposable blood pump (centrifugal type) for temporary use were used. A simple mock circulation test (5L/min, 100 mmHg) was performed to investigate with both whole-blood samples and platelet-poor plasma (PPP) using fresh bovine blood. Results In an analysis based on SDS-agarose gel electrophoresis and serum VWF values (antigen and activity), high-molecular-weight multimers (HMWMs) in VWF are reduced immediately after the initiation of blood circulation using the axial flow pump, and it had plateaued 60 minutes later. On the other hand, in the study using a centrifugal pump, cleavage of the HMWMs compared to that in the case of using a centrifugal pump was very slight. Moreover, in the whole-blood sample study, HMWMs reduced once, and it had been observed to recover after 60 minutes. However, HMWMs in the PPP sample was observed to reduce continuously during a circulation test. Conclusion In this result, the dynamics of VWF within the blood pump was shown to depend on the type of the blood pump, and this study demonstrated that re-supply of VWF due to platelet activation and cleavage of VWF due to shear stress in the pump occurred at the same time by circulating within the blood pump.

Predictive and Prognostic Value of Von Willebrand Factor in Patients with Cirrhosis and Esophageal Varices

Background and study aim: Von Willebrand factor (vWF) is released by activated endothelial cells and plays a crucial role in the development of portal hypertension. vWF levels correlate with liver function and venous hepatic pressure gradient (VHPG) and independently predict clinical outcome. The aim was to evaluate serum vWF levels as a predictor for esophageal varices and prognosis in patients with liver cirrhosis. Patients and Methods: Sixty two patients with liver cirrhosis, divided into two groups according to presence (group I) or absence (group II) of varices were included, In addition, twenty healthy persons served as control group (group III). All patients were submitted to full history taking, clinical examination, laboratory investigations and abdominal ultrasonography. The severity of liver disease was estimated by Modified Child-Pugh and Model for End Stage Liver Disease (MELD) scores. All patients were underwent upper gastrointestinal endoscopy and vWF assay. Results: vWF values were significantly higher in group I (p1=0.001), than controls (p2=0.000), but no significant difference between group II and control group (p3= 0.59). Receiver operating characteristics (ROC) curve analysis of vWF revealed that, vWF at cutoff value of 173.8 µg/ml; the sensitivity for detection of esophageal varices was 80.8%, specificity 76.0%, positive predictive value (PPV) was 93.9%, negative predictive value (NPV) was 55.6%; area under the curve was 86.6.There was significant positive correlation between vWF and Child, MELD, esophageal varices grade and severity of portal hypertensive gastropathy. Conclusion: vWF is a good predictor for development of esophageal varices and correlated well with prognosis in patients with cirrhosis.

Rituximab (R)-CHOP Therapy Has Progressed Arteriosclerosis with an Elevation of Von Willebrand Factor (vWF) in Patients with Malignant Lymphoma

Introduction: An increased incidence of arteriosclerosis has been noted in cancer survivors. Until now, only a few reports have been reported on relationship between arteriosclerosis and chemotherapy. As a mechanism for developing arteriosclerosis by chemotherapy, reduction of nitric oxide from endothelial cells has been reported. We have reported a case who was 68-year-old female with follicular lymphoma, clinical stage IVA showing the plaque formation of carotid artery and the elevation of cardio-ankle vascular index (CAVI) after eight courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) without complication of diabetes mellitus and hyperlipidemia (2017, JCMR). In this study, we evaluated the incidence of developing arteriosclerosis with chemotherapy using CAVI as an arterial stiffness parameter, carotid artery ultrasonography and the value of von Willebrand factor (vWF) as an endothelial damage in patients with malignant lymphoma who were treated with R-CHOP therapy.Materials and methods: Between March 2017 and February 2018, thirteen patients with B-cell malignant lymphoma who were treated with R-CHOP chemotherapy were enrolled after obtaining written informed consent. We evaluated the arteriosclerosis with CAVI index, carotid artery ultrasonography and the value of vWF during each chemotherapy. This study was approved by the Ethics Committee of Toho University.Results: Twelve men and one woman were registered (the median age, 73 years old, range, 59 - 82). One patient was treated with 4 courses of R-CHOP followed by irradiation and the remaining 12 patients were treated with 6-8 courses of R-CHOP. All patients achieved complete remission. The mean value of vWF was significantly elevated from 147 ± 40.0 % to 192 ± 39.8 % after one course of R-CHOP (p = 0.001). Then, the value of vWF was elevated significantly at the each time point compared with the pretreatment value (after 3 cycles; 190 ± 53.5, p = 0.0017, 6 cycles; 198 ± 32.5, p = 0.0024) (Figure 1). The value at after the final chemotherapy (175 ± 41.3) decreased significantly comparing the value of final treatment (207 ± 38.9, p = 0.0112). Nine patients showed the progression of arteriosclerosis with new plaque formation or progression of intima-media thickness by carotid artery ultrasonography. Plaque score after completing the therapy was elevated significantly from 6.4 ± 4.33 to 6.8 ± 4.65 (p = 0.0313) as shown in Figure 2. Some patients showed the elevation of CAVI index with the progression of treatment. However, there was no significant elevation of the index during the treatment.Conclusions: We reported that malignant lymphoma patients showed the significant elevation of vWF and new plaque formation in carotid artery during the R-CHOP therapy. vWF elevation might have progressed the arteriosclerosis in the patients with R-CHOP therapy. Further study will be required to clarify the relationship between chemotherapy and arteriosclerosis. DisclosuresNo relevant conflicts of interest to declare.

Utility of Repeat Testing in the Evaluation for Von Willebrand Disease in Pediatric Patients

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is diagnosed via 3 cardinal features: 1) personal history of bleeding, 2) laboratory assays and 3) family history of VWD. The diagnosis of VWD in pediatric patients is complicated by von Willebrand factor (VWF) inter- and intra-assay variability, phlebotomy-induced physiologic stress increasing VWF levels from baseline, and a lack of prior hemostatic challenges. Given these challenges, NHLBI guidelines recommend repeated testing in patients with mildly low or normal levels and a high suspicion of VWD. However, no studies to date have evaluated the utility of repeat VWF testing in pediatric patients. Currently, our center's standard of care is to complete 3 separate sets of VWF testing to rule out VWD. The primary objective of this study was to determine the clinical variables associated with requiring more than 1 test to diagnose VWD and to establish a cutoff value for the first set of VWF assays above which further testing would not be informative.This single center retrospective cohort study included patients ≤ 18 years of age who either had a diagnosis of or evaluation for VWD between January 2012 and July 2017. Patients were excluded if the VWD laboratory evaluation was completed at another institution or due to the presence of another bleeding disorder. Medical charts were abstracted for demographic information, medications, reason for testing, family history of VWD, results of VWF assays, and other illness at time of evaluation. All patients had a retrospective ISTH BAT score completed. Data were analyzed using SAS and are reported as median (IQR). Statistical analysis was done with non-parametric tests (Mann-Whitney or Wilcoxon sign-rank) for two groups comparisons. Odds ratios were calculated using Fisher's Exact test for clinical factors associated with a VWD diagnosis. Univariate logistic regression was performed, modeling the odds of requiring more than 1 diagnostic test to diagnose VWD.One thousand unique patients were evaluated and 189 excluded, yielding a final cohort of 811 patients. Of these, 631 (77.8%) did not have VWD and 180 (22.2%) were diagnosed with VWD. Patients diagnosed with VWD were younger than those without (median age 5.8 vs 8.5 years, p=0.0019) and were more likely to have a family history of VWD (38% vs 22%, p < 0.0001) but there was no difference in race or sex between cohorts. As expected, patients in the VWD cohort had lower VWF activity (34 vs 78 IU/dl, p < 0.0001), VWF antigen (45 vs 89 IU/dL, p < 0.0001) and FVIII (57 vs 100 IU/dL, p < 0.0001) than those without VWD. ISTH BAT scores were higher in the VWD cohort (2.47 vs. 2.07, p = 0.027).As shown in Table 1 and Figure 1, increased odds of VWD diagnosis were noted in those tested due to a family history of VWD (OR 1.75, 95% CI 1.21-2.51) or abnormal coagulation studies (OR 1.61, 95% CI 1.07-2.24). Subjects with VWD required fewer tests than those without VWD (median 1 vs 2, p < 0.001).Univariate analysis failed to identify any significant associations with needing > 1 test for the diagnosis of VWD (Table 1), so a multivariable model was not performed. In 69.4% (125/180) of subjects with VWD, the first test was diagnostic.In receiver-operating curve analysis, the first VWF antigen and activity have a high power for diagnosis of VWD with AUC of 0.88 and 0.92, respectively (Fig 1). A cutoff of 100 IU/dL for VWF antigen or activity on first test yielded a sensitivity of 95%, specificity of 38% and negative predictive value of 96.6% for VWF antigen compared to 98%, 38% and 98.6% for VWF activity, respectively.Here we demonstrate that the majority of pediatric subjects had diagnostic VWF values on the first set of testing. Unfortunately, no clinical variables were identified for patients with VWD who required > 1 test for diagnosis. However increased odds of VWD diagnosis were noted in those with a family history of VWD and abnormal coagulation studies. A cutoff of 100 IU/dL for VWF activity or antigen on the first test resulted in > 95% negative predictive value to rule out the diagnosis. Pediatric patients without a family history of VWD and VWF levels > 100 IU/dL on initial test may not need further testing to rule out the diagnosis of VWD. DisclosuresDoshi:Bayer Hemophilia Awards Program: Research Funding. Butler:Pfizer: Consultancy; Genentech: Consultancy; HemaBiologics: Consultancy.

Prognostic value of von Willebrand factor in patients with atrial fibrillation: A meta-analysis.

Background:Studies on the prognostic role of von Willebrand factor (vWF) in patients with atrial fibrillation (AF) are conflicting. This meta-analysis aimed to evaluate the association of elevated circulating vWF level with adverse outcomes in patients with AF.Methods:PubMed and Embase were used to search literature through August 2017. Prospective observational studies that evaluated the association of elevated vWF level with major adverse cardiac events (MACEs) and all-cause mortality in patients with AF were deemed eligible. The MACEs included death, stroke/transient ischemic attack, heart failure, myocardial infarction, and systemic/peripheral embolism.Results:A total of 6 studies were included this meta-analysis. Patients with AF with the highest vWF level were independently associated with greater risk of MACEs (risk ratio [RR] 2.20; 95% confidence intervals [CI] 1.61–3.01) and all-cause mortality (RR 1.63; 95% CI 1.39–1.91). Subgroup analysis showed that the prognostic role of higher vWF level was consistently observed in each defined subgroups.Conclusion:Patients with AF with elevated vWF level are independently associated with a higher risk of MACEs and all-cause mortality. However, more well-designed prospective studies are needed to confirm these findings.

A predictive value of von Willebrand factor for early response to Bevacizumab therapy in recurrent glioma.

Bevacizumab (BV), a neutralizing monoclonal antibody against the vascular endothelial growth factor ligand, is recognized as a potent anti-angiogenic agent with antitumor activity. The aim of this single-center, retrospective, longitudinal study was to investigate the possible predictive value of baseline demographic, clinical and laboratory parameters for early 3-month response to BV therapy in patients with recurrent glioma. Forty-nine patients with recurrent glioma received BV at 10mg/kg intravenously every 3weeks alone or in association with chemotherapy were included in this study. Blood samples were collected from all patients before the first (baseline), the second and the third administration of BV. After 3months of BV therapy, patients with partial response were defined as responders whereas patients with stable or progressive disease were defined as non-responders. The median overall follow-up was 8months (range 1-73), the median overall survival (OS) was 8months (95% CI 6-10) and the median progression free survival (PFS) was 4months (95% CI 3-5). Thirty-five % of patients were responders and showed significantly lower von Willebrand factor (VWF) levels than non-responders at all sample times (p < .02 for all). Also, on multivariate analysis the baseline VWF value was the only predictor for an early response to BV therapy. Furthermore, D-dimer and prothrombin fragment 1+2 were predictive factors for OS while Karnofsky performance status resulted predictive for PFS. VWF antigen value is a possible predictive biomarker for an early 3-month response to BV therapy in recurrent glioma.

Acquired Von Willebrand syndrome in patients on long-term support with HeartMate II.

Impaired binding of Von Willebrand factor (VWF) to platelets and to collagen due to acquired Von Willebrand syndrome (AVWS) is associated with support from a ventricular assist device (VAD) and can contribute to bleeding tendencies in patients with VADs. The onset of AVWS has been shown to occur immediately after VAD implantation. Our aim was to determine long-term data on AVWS in VAD patients. We analysed 278 data sets of 74 patients on HeartMate II (HMII) support for 3-80 months after implantation (11.2 ± 12.1, median 6.3 months.). Ristocetin cofactor activity (VWF:RCo), collagen binding capacity (VWF:CB), VWF antigen (VWF:Ag) and the ratios of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were determined. Further, the presence of high molecular weight (HMW) multimers of VWF was investigated. Abnormally low values of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were found in 69% and 97% of blood samples, respectively. Only ten of 181 multimer analyses showed a normal pattern, and HMW multimers were present in both specimens in only one of the 74 patients. No significant changes in these parameters were observed over time. The VWF:CB/VWF:Ag ratio correlated with the multimer patterns, whereas the VWF:RCo/VWF:Ag ratio seemed to be less sensitive for AVWS. Our data indicate that AVWS is a typical phenomenon in patients with VAD support and that there are no time-dependent changes in these parameters apparent in most patients on long-term support with HMII.

Acquired Von Willebrand Syndrome (AVWS) Type 2A as the Presenting Feature of JAK2 Wild type Thrombocythemia in a Child: Effectiveness of Platelet Reduction by Anagrelide

A 9-year-old Caucasian boy presented in 1994 with severe headache, attacks of migraine, aggressive behavior and minor bleeding symptoms. Initial abnormal laboratory data were a platelet count of 1596 × 109/L and slight splenomegaly on echogram. Low-dose aspirin 100 mg/day relieved the cerebral symptoms, but a pronounced spontaneous bleeding tendency became evident. Severe epistaxis, bruises, hematomas and gum bleedings resulted in an iron deficiency state (hemoglobin 5.7 mmol/L,hematocrit 0.30, MCV 77 fl, ferritine 6 ug/l) in November 1995. The combination of mucocutaneous bleeding, high platelet counts (1946 × 109/L), and increase of enlarged megakaryocytes in a bone marrow smear was consistent with the diagnosis of hemorrhagic thrombocythemia. Coagulation studies revealed the presence of an acquired von Willebrand syndrome type 2A featured by a prolonged Ivy bleeding time, near normal factor VIII coagulant activity (0.53 u/ml) and von Willebrand factor (VWF) antigen (0.55 u/ml), low VWF ristocetine cofactor activity (0.29), very low VWF collagen binding activity (0.16 u/ml) and absence of large VWF multimers. A severe epistaxis lasting for several hours stopped immediately after correction of the VWF parameters by substitution of 3000 units Bone marrow histopathology showed a pronounced increase of large immature megakaryocytes with hyperlobulated nuclei and maturation defects of nuclei and cytoplasm, and absence of reticuline fibrosis consistent with the diagnosis of JAK2 wild type thrombocythemia in primary megakaryocytic granulocytic myeloproliferation (PMGM). Initial treatment with hydroxyurea (500 mg daily) followed by anagrelide resulted in correction of platelet count from 2000 × 109/L to near normal (400-600 × 109/L) by), which was associated with relief of bleeding symptoms, and correction of plasma VWF values and VWF multimeric pattern to normal. The subsequent natural history was featured by spontaneous reduction of platelet count to near normal and no progression of JAK2 wild type myeloproliferative neoplasms for more than 13 years follow-up.

Severe Reduction of Free ADAMTS13, Unbound to Von Willebrand Factor, in Plasma Milieu Is a Unique Feature of HELLP Syndrome

IntroductionPlasma ADAMTS13 exists at least two forms, bound and unbound to vonWillebrandfactor (VWF), of which the former was assumed to be 3% of the total by the immunoprecipitation method (Feyset al., JTH 2009). We have shown that plasma ADAMTS13 consists of 3 group bands, by means of isoelectric focusing (IEF) analysis (Hori et al, Transfusion 2013). Band I (pI4.9-5.6) was assumed to be free ADAMTS13, unbound to VWF, and Band III (pI7.0-7.5) was a complex with high-molecular-weight VWFmultimers(HMW-VWFM). However, the feature of Band II (pI5.8-6.7) was undetermined.HELLP (hemolysis, elevated liver enzymes and low platelet counts) syndrome is a life-threatening thromboembolic complication during pregnancy, and its pathogenesis is not determined. The curative therapy of HELLP syndrome is a termination of pregnancy. It was reported that plasma VWF antigen (VWF: Ag) was remarkably increased (215-422% of the normal) with a mild reduction of ADAMTS13 activity (ADAMTS13: AC) (12-43 % of the normal), but without qualitative analysis of ADAMTS13 antigen (Lattuadaet al.,Haematologica2003).We here analyzed plasma ADAMTS13 antigen in 9 patients with HELLP syndrome using the IEF gel, and revealed a unique picture of severe reduction of Band I (free ADAMTS13), unbound to VWF, that was not seen in plasmas from normal pregnancy.Patients and MethodsOne hundred twenty-nine normal pregnant women and 9 patients with HELLP syndrome were analyzed under approval by the ethics committees of Nara Medical University. All individuals gave written informed consent to the study. Diagnosis of HELLP syndrome was made by all the following laboratory abnormalities: characteristics peripheral blood smear, serum LDH >600 IU/L (or total bilirubin >1.2 mg/dL), AST >70 IU/L, and platelet counts < 100,000/mm3 (Sibai et al., Am JObstetGynecol 1993). Plasma level of ADAMTS13: AC was determined by chromogenic ADAMTS13-act-ELISA, and VWF: Ag was measured by a sandwich ELISA using a rabbit polyclonal anti-human VWF antibody. As reported previously (Hori et al., Transfusion 2013), the IEF was performed using a large-pore agarose-acrylamide composing gel followed by detection with anti-ADAMTS13 monoclonal antibody.ResultsIn normal women, plasma levels of VWF: Agweremarkedly increased during pregnancy, and the values of third trimester (median 223%) were almost two times higher than those of first trimester (119%). Contrarily,plasma levels ofADAMTS13: AC were significantly decreased in second (68.4%) and third (66.2%) trimester compared with first trimester (84.3%, p<0.01 and p<0.001, respectively). Of note, a reduction in ADAMTS13: AC was significantly prolonged in postpartum period (50.2%, p<0.001), while increased VWF: Ag was rapidly recovered after delivery. Further, the IEF analysis of normal pregnant women showed that Band I was slightly decreased in accord with progression of pregnancy.In puerperium, there was no difference in ADAMTS13: AC between normal pregnant women and patients with HELLP syndrome. However, the values of VWF: Ag of patients with HELLP syndrome (352%) were significantly higher than those of normal pregnant women (178%, p<0.001), in agreement with a previous report. Interestingly, however, here we have shown that 7 out of 9 patients with HELLP syndrome showed severe reduction of Band I in puerperium period by the IEF analysis of ADAMTS13 (Figure).DiscussionIn normal pregnant women, the decreased ADAMTS13:AC was assumed to reflect a consumption of the enzyme for cleavage of increased VWF. Interestingly, both Band II and III were almost unchanged during normal pregnancy, but Band I slightly decreased in third trimester, concomitantly with a mild reduction of ADAMTS13:AC. In contrast, Band I was severely reduced during the acute phase of HELLP syndrome in 7 out of 9 patients.Our previous report indicated that under high-shear-stress Band I inhibited the VWF-dependent platelet aggregation in a dose-response manner from the initial phase, whereas Band III (+II) worked from the later phase. This result indicates that ADAMTS13 lacking Band I neither readily binds to VWF nor efficiently blocks the heightened high-shear-stress induced platelet aggregation generated by newly produced HMW-VWFM. Our data suggest that ADAMTS13 preparation might be used as a therapeutic option for the treatment of HELLP syndrome, before termination of pregnancy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Common bleeding disorders affecting individuals with Hereditary Hemorrhagic Telangiectasia.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder affecting vasculature in different organ systems; seen at a rate of approximately 1:5000 in North America. Complications, with significant increases in health service utilization, arise from bleeding and shunts, and are particularly problematic in the lung and liver. Although these patients tend to chronically bleed from the GI tract and nasal cavities, a single bleed from arterio-venous malformations in the lungs or brain can have serious health implications and may be fatal. Bleeding due to vascular wall fragility in HHT patients can be further complicated with a concomitant bleeding disorder. The proportion of adult patients seen in the Edmonton HHT center with a concomitant bleeding disorder, as assessed by blood test results for Factor VIII and related factors (Ristocetin Cofactor), Factor IX and Factor XI, was determined in a retrospective, single centre study. Of 77 individuals with HHT, four had below normal values of von Willebrand Factor, Ristocetin Cofactor or Factor VIII. Two patients had laboratory parameters diagnostic of a bleeding disorder, accounting for 2.6% of confirmed HHT subjects. These results indicate that establishing screening for bleeding disorders in HHT centers is important in managing bleeding symptomatology. In individuals with HHT, the presence of a second bleeding disorder can have significant clinical implications on patient management and health care utilizations. This paper highlights areas that need to be reviewed with respect to best practice protocols for the management of HHT patients.

The Successful Use of Desmopressin With Tranexamic Acid in Children With Mild Type 1 Von Willebrand Disease Who Undergo Circumcision

Background: Desmopressin (DDAVP) is a synthetic vasopressin analog, and increases endogenous von Willebrand factor (VWF) by secreting it from the vascular endothelial cell. Circumcision is one of the oldest and most commonly performed operations in the world. This study reported the specific uses of DDAVP together with tranexamic acid in children with mild type 1 von Willebrand disease (VWD) undergoing circumcision. The aim of this study was to report the successful use of DDAVP in two doses and tranexamic acid in six children with VWD undergoing circumcision. Methods: Our study evaluated two doses of DDAVP therapy in circumcision operation of six male children diagnosed with mild type 1 VWD with a good response to DDAVP before they underwent circumcision, with a mean age of 7.3 years. The subcutaneous preparation of DDAVP was utilized. Under medical supervision, patients were subcutaneously injected DDAVP at a dose between 0.3 and 0.2 μg/kg based on their weight. Oral tranexamic acid was instituted at a dosage of 15 mg/kg three times per day for 5 days. The first dose was given 24 hours before circumcision. The first and second doses of DDAVP were given 1 hour before the circumcision and 24 hours after the circumcision, respectively. Results: This study included six male children aged 4 - 10 years with mild type 1 VWD, weighting 22 - 30 kg. The DDAVP dose (mean, range) based on the patient’s weight was 0.25 (0.23 - 0.28 μg/kg). The calculated dose was repeated two times for each patient. Laboratory values (mean, range, U/dL) of baseline VWF:Ag, VWF:RCo and FVIII:C in mild type 1 VWD patients were 37 (32 - 42), 38 (34 - 42), and 50 (44 - 56), respectively. Conclusion: Single infusions of DDAVP for common bleeding episodes do not usually require laboratory monitoring. There are limited published data to guide clinical practice about the optimal dosing and timing of these agents to prevent or resolve bleeding using DDAVP at minor surgeries as circumcision operation. Castaman et al showed almost all minor surgeries and deliveries occurring during follow-up were successfully managed with DDAVP in patients with type 1 VWD. We used two doses in circumcision like O’Brein. Comparison of the results across studies is difficult, as surgical techniques, timing, and frequency of DDAVP dosing, and use and dosing of antifibrinolytics all varied by institution. Two doses of DDAVP allowed adequate perioperative bleeding prophylaxis management in children with mild type 1 VWD who underwent circumcision surgery with presenting bleeding complications. Int J Clin Pediatr. 2015;4(4):181-183 doi: http://dx.doi.org/10.14740/ijcp228e

Reliability of Plasma Von Willebrand Factor Antigen in Prediction of Esophageal Varices in Patients with Liver Cirrhosis

Background: Bleeding esophageal varices (OVs) due to portal hypertension are one of the major complications with high mortality in liver cirrhosis. So, early detection and management are mandatory. Aim: To evaluate the role of Von Willebrand factor (VWF) in predicting the presence of OVs. Patients and Methods: 62 patients with liver cirrhosis representing different Child-Pugh classes were included. The diagnosis of liver cirrhosis was based on the combination of clinical, laboratory and US examinations. All included patients underwent the following investigations: complete blood count, liver function tests (ALT, AST, serum bilirubin, albumin and total protein, prothrombin time (PT) and concentration (PC), INR and serum alkaline phosphatase), serum creatinine, Von Willebrand factor antigen (VWF-Ag) measurement and abdominal US. Upper endoscopic evaluation was done to detect presence or absence of varices (esophageal or gastric) and/or PHG. Results: 38 males and 24 females with their mean age (46 ± 12 years old) were included. Plasma Von Willebrand factor-Ag level was significantly higher in patients with OVs than those without varices (P value = 0.000). Also, its level was significantly higher in patients with higher grade of OVs, G3 than those with G1 or G2 (P value = 0.000). Patients with large OVs including those with G2 and G3 showed significantly higher values of VWF than those with small OVs (NO and G1) (P value = 0.000). VWF was independent predictor for detecting the presence of OVs with good sensitivity (90), specificity (77.3) and accuracy (85.5) at a cutoff value of 1.74 U/ml. Also it was an independent predictor for detecting the presence of large OVs with good sensitivity (91.2), specificity (85.7) and accuracy (88.7) at a cutoff value of 2.16 U/ml. Conclusion: VWF-Ag could be used as a non invasive laboratory independent predictor for the detection of OVs.

The Diagnostic Value of Plasma Level, Activity, Ratios between von Willebrand Factor and ADAMTS13 in Patients with Cerebral Infarction

Introduction: Large population studies have revealed that higher levels of von Willebrand Factor (VWF) and lower levels of ADAMTS13 activity (ADAMTS13) are associated with a risk of thrombosis. In this study, we aimed to investigate the relationship among the plasma levels of VWF, ADAMTS13 and the occurrence of cerebral infarction in patients.Methods: In a case-control study of 94 cerebral infarction patients (CIP) and 103 age-matched healthy controls (Control), the plasma levels of VWF antigen (VWF:Ag ), VWF ristocetin cofactor activity (VWF:Rcof), and VWF collagen binding activity (VWF:CB) were measured using ELISA. ADAMTS13 activity (ADAMTS13) was measured with FREST-VWF73. The study was approved by the institutional Ethics Committee at the First Affiliated Hospital of Soochow University, China. All participants were given write informed consents.Results: The levels of VWF:Ag and VWF:Rcof in cerebral infraction patients (mean±SEM, 223±15% and 256±20%) were significantly higher compared with controls (117±8% and 128±9%). Levels of ADAMTS13 and ratios of VWF:CB/VWF:Ag, ADAMTS13/VWF:Ag and ADAMTS13/VWF:Rcof in patients (107±4%, 0.73±0.08, 0.76±0.07 and 0.86±0.10, respectively) were significantly lower compared with controls (125±3%, 1.37±0.08, 1.69±0.14 and 1.45±0.10, P<0.001, respectively). However, there was no difference between cerebral infarction patients and controls in the levels of VWF:CB, VWF:Rcof/VWF:Ag and ADAMTS13/VWF:CB (P>0.05). Unconditional logistic regression analysis demonstrated the highest quartile of VWF:Ag (odds ratio [OR] = 5.11, 95% confidence interval [CI], 1.49-17.50), VWF:Rcof (OR = 5.04, 95% CI, 1.62-15.66), and the lowest quartile of VWF:CB/VWF:Ag (OR = 5.91, 95% CI, 1.95-17.93), ADAMTS13/VWF:Ag (OR = 9.11, 95% CI, 2.49-33.33), ADAMTS13/VWF:Rcof (OR = 3.73, 95% CI, 1.39-10.03) were associated with cerebral infarction (P<0.01). The receiver operating characteristic (ROC) curves analysis demonstrated the cutoff values of VWF:Ag (137.88%), VWF:Rcof (135.88%) and VWF:CB/VWF:Ag (0.538), ADAMTS13/VWF:Ag (0.974), ADAMTS13/VWF:Rcof (0.946) showed a better diagnostic value of cerebral infarction (AUC > 0.7).Conclusions: High levels of VWF:Ag, VWF:Rcof and lower levels of VWF:CB/VWF:Ag, ADAMTS13/VWF:Ag, ADAMTS13/VWF:Rcof are relative risk factors. The threshold of VWF:Ag ( > 137.88%), VWF:Rcof ( > 135.88%), VWF:CB/VWF:Ag ( ≤ 0.538), ADAMTS13/VWF:Ag ( ≤ 0.974), ADAMTS13/VWF:Rcof ( ≤ 0.946) can be diagnostic indicators of cerebral infarction.Research funding: This work was supported by grants from National Scientific Foundation of China (NSFC) (81270593), Jiangsu Provincial Special Program of Medical Science (BL2012005) and Jiangsu Province’s Key Medical Center (ZX201102), China DisclosuresNo relevant conflicts of interest to declare.