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Concept: Heyde's syndrome


Type 2 diabetes is known to cause endothelial activation resulting in the secretion of von Willebrand factor (VWF). We have shown that levels of VWF in a glycoprotein Ib-binding conformation are increased in specific clinical settings. The aim of the current study is to investigate whether active VWF levels increase during aging and the development of diabetes within the population of patients suffering from type 2 diabetes. Patients and controls were divided into two groups based on age: older and younger than 60 years of age. VWF antigen, VWF propeptide, VWF activation factor and total active VWF were measured. Patients older than 60 years of age had increased levels of total active VWF, VWF activation factor and VWF propeptide compared to younger patients and controls. All measured VWF parameters were associated with age in diabetic patients. Total active VWF and VWF propeptide correlated with the period of being diagnosed with diabetes. Regression analyses showed that especially the VWF activation factor was strongly associated with diabetes in patients older than 60 years of age. In conclusion, we found that the conformation of VWF could be involved in the disease process of diabetes and that the VWF in a glycoprotein Ib-binding conformation could play a role as risk marker during the development of diabetes in combination with an increase in age. Our study shows that the active quality of VWF was more important than the quantity.

Concepts: Heyde's syndrome, Diabetes mellitus, Weibel-Palade body, Insulin, Diabetes mellitus type 2, Platelet, Von Willebrand disease, Von Willebrand factor


We developed a novel murine monoclonal antibody (mAb) against the C-terminal α-helix of the human von Willebrand factor A2, designated SZ-179. We showed that SZ-179 inhibited the interactions between VWF and ADAMTS13 and prevented the degradation of high molecular weight VWF multimers. Importantly, SZ-179 reduced the proteolysis of VWF-R1597W mutant by rADAMTS13 dose-dependently under native conditions. Our findings reveal a potential therapeutic target for bleeding disorders.

Concepts: Immunohistochemistry, Blood, Bernard-Soulier syndrome, Heyde's syndrome, Monoclonal antibody therapy, Von Willebrand disease, Monoclonal antibodies, Von Willebrand factor


BACKGROUND: The von Willebrand factor (VWF) gene is highly polymorphic, with variants correlated with VWF antigen levels, adhesion activity, clearance, and factor VIII binding. VWF mutations are detected in patients with von Willebrand disease (VWD), whereas polymorphic variants could be associated with thrombosis. However, information on the ethnic diversity of VWF variants and their association with diseases is limited. OBJECTIVES: To characterize novel VWF variants from different ethnicities in the general population. Patients/Methods: We analyzed samples from 1,092 subjects of 14 ethnicities available in the 1000 Genomes database for VWF variants and their potential functional impacts RESULTS: We identified 2,728 SNPs and 91 insertions and deletions that had a high level of ethnic diversity, with Africans having the highest number of variants. The highest level of diversity was found in the D' and D2 domains. Among 94 non-synonymous variants, 31 were predicted to be deleterious, including 19 that were previously associated with VWD. Most of these “VWD variants” had allele frequencies consistent with disease incidence in European subjects; but some had a significantly higher frequency in other ethnicities. The mutation R2185Q, H817Q and M740I associated with type 1 and type 2N VWD were present in more than 13% of African subjects. CONCLUSIONS: These results highlight the complexity of VWF variations in different ethnic groups and emphasize the importance of interrogating variations on multiple ethnic backgrounds for associations with bleeding and thrombosis. © 2012 International Society on Thrombosis and Haemostasis.

Concepts: Weibel-Palade body, Ristocetin induced platelet agglutination, Heyde's syndrome, Platelet, Von Willebrand disease, Von Willebrand factor


While von Willebrand factor (vWF) has been reported to be elevated in smokers, there are no reports on the effects of smoking on its cleaving protease ADAMTS-13, particularly in subjects of Arab ethnicity. This study was conducted to determine the effects of smoking on vWF and ADAMTS-13 antigen and activity levels in Arab males. Venous blood samples from 80 smoking (at rest) and 80 non-smoking healthy males were collected after asking subjects to fast and refrain from smoking for 8 hours. Similar sampling was done for 40 smokers (acute smokers), who were asked to smoke one cigarette immediately before blood collection. Plasma was used to measure ADAMTS-13 antigen and activity levels, as well as vWF antigen and collagen binding activity levels using commercial ELISA kits. Compared to non-smokers, ADAMTS-13 and vWF activities were significantly lower in smokers at rest (p < 0.05). Acute smokers had significantly higher levels of vWF activity and ADAMTS-13 antigen and activity levels (p < 0.01), compared to smokers at rest. Our results suggest that high vWF activity is accompanied by an increase in ADAMTS-13 activity as a natural physiological mechanism to degrade the elevated vWF molecules. If not followed by a subsequent smoke, the activities of both proteins subside. It is possible that the repeated increase in vWF and constant degradation by ADAMTS-13 results in lower overall levels of both proteins in smokers (at rest) compared to nonsmokers who do not experience a similar (repeated) injury to the endothelium.

Concepts: Heyde's syndrome, ABO blood group system, Weibel-Palade body, Platelet, Hematology, Von Willebrand disease, Blood, Von Willebrand factor


Apart from TTP, ADAMTS13 may be an important player in those conditions where Von Willebrand Factor and the Platelet Glycoprotein GP Ib axis have a part to play in the pathogenesis. This includes stroke, myocardial infarction, sepsis and inflammatory condition. This article reviews the literature in these conditions.

Concepts: Aspirin, Heyde's syndrome, Atherosclerosis, Myocardial infarction, Von Willebrand disease, Platelet, Thrombotic thrombocytopenic purpura, Von Willebrand factor


Emerging evidence supports the concept of a rebalanced hemostatic state in liver disease as a result of a commensurate decline in pro- and antihemostatic drivers. In the present study, we assessed levels and functionality of the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 in plasma of patients with acute liver injury and acute liver failure (ALI/ALF). Furthermore, we explored possible associations between VWF, ADAMTS13 and disease outcome. We analysed plasma of 50 patients taken on the day of admission for ALI/ALF. Plasma of 40 healthy volunteers served as controls. VWF antigen levels were highly elevated in patients with ALI/ALF. In contrast, the collagen binding activity and the ratio of the VWF ristocetin cofactor activity and VWF antigen was significantly decreased when compared to healthy controls. Also, the proportion of high molecular weight VWF multimers was reduced, despite severely decreased ADAMTS13 levels. In spite of these functional defects, platelet adhesion and aggregation were better supported by plasma of patients with ALI/ALF when compared to control plasma. Low ADAMTS13 activity, but not high VWF antigen, was associated with poor outcome in patients with ALI/ALF as evidenced by higher grades of encephalopathy, higher transplantation rates and lower survival. VWF or ADAMTS13 levels were not associated with bleeding or thrombotic complications. Conclusion: highly elevated levels of VWF in plasma of patients with ALI/ALF support platelet adhesion, despite a relative loss of function of the molecule. Furthermore, low ADAMTS13 activity is associated with progressive liver failure in the patient cohort, which might be attributed to platelet-induced microthrombus formation in the diseased liver resulting from a substantially unbalanced VWF/ADAMTS13 ratio. (HEPATOLOGY 2013.).

Concepts: Hepatology, Coagulation, Thrombotic thrombocytopenic purpura, Heyde's syndrome, Hemostasis, Platelet, Von Willebrand disease, Von Willebrand factor


The association between angiodysplasia and von Willebrand disease (VWD) has been known for more than 40 years. Bleeding in the gastrointestinal tract associated with angiodysplasia worsens the clinical course of this inherited haemorrhagic disorder and management may become difficult and challenging. Angiodysplasia associated with acquired defects or dysfunctions of von Willebrand factor (VWF) has also been reported in a variety of conditions such as monoclonal gammopathies, Heyde syndrome and in carriers of ventricular assist devices. The most recent advances concerning the mechanistic, clinical and therapeutic aspects of VWD-associated angiodysplasia are summarized in this review, together with the limitations of our knowledge that warrant further research in the frame of international cooperation.

Concepts: Platelet, Aortic valve stenosis, Heyde's syndrome, Von Willebrand disease, Von Willebrand factor


Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy which causes significant morbidity and mortality unless promptly recognized and treated. The underlying pathogenesis of TTP is a severe deficiency in ADAMTS13 activity, a metalloprotease that cleaves ultralarge von Willebrand factor multimers. This deficiency is either autoantibody mediated (acquired TTP) or due to deleterious mutations in the gene encoding ADAMTS13 (congenital TTP). The elucidation of this disease mechanism has reinforced the rationale and place of current therapies (eg, plasma exchange) as well as providing a basis for the prospective evaluation of immunotherapy with rituximab in addition to classic immunosuppression (eg, corticosteroid) in autoantibody-mediated TTP. This review discusses the current evidence base for therapeutic interventions in acquired and congenital TTP as well as providing a practical approach to the other aspects of investigation and management for which a firm evidence base is lacking. Novel agents that are currently being evaluated in prospective trials and future directions of therapy are also discussed which are expected to make an important contribution to improving outcomes in patients with TTP.

Concepts: Heyde's syndrome, ADAMTS13, Von Willebrand disease, Therapy, Platelet, Idiopathic thrombocytopenic purpura, Von Willebrand factor, Thrombotic thrombocytopenic purpura


The knowledge gained from “experiments of nature” has always been paramount in identifying key players in pathophysiologic pathways. This is well characterized by naturally occurring bleeding and thrombotic disorders. In most cases, it is the absence of a particular protein that leads to recognition of its importance for normal physiology. On the other hand, gain-of-function mutations highlight not only the presence of the protein, but also how it regulates a particular physiologic response. In this issue of the JCI, Casari and colleagues define a previously unrecognized consequence of variant type 2B von Willebrand factor (vWF) binding to blood platelets. More than 30 years after an initial description of type 2B variant vWF, the consequence of this spontaneous variant vWF binding to platelets is viewed as a dysregulation of platelet signaling pathways contributing to the type 2B bleeding phenotype.

Concepts: Heyde's syndrome, Thrombotic thrombocytopenic purpura, Hemostasis, Blood, Coagulation, Platelet, Von Willebrand disease, Von Willebrand factor


Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterised; however their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOEC) from peripheral blood of four type 1 VWD, four type 2 VWD patients and nine healthy controls. We confirmed the endothelial lineage of BOEC, then measured VWF mRNA and protein levels, both before and after stimulation, and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However BOEC from this group of patients also showed defects in processing, storage and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOEC from three type 2 VWD patients, supporting the dysfunctional VWF model. However, one type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into the cellular mechanisms of the disease.

Concepts: Aortic valve stenosis, Heyde's syndrome, Bernard-Soulier syndrome, Platelet, Weibel-Palade body, Von Willebrand disease, Coagulation, Von Willebrand factor