Materiały źródłowe

• #1 Von Willebrand Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459222/

  Von Willebrand disease is a bleeding disorder caused by the qualitative or quantitative deficiency of the pro-von Willebrand factor. […] Von Willebrand factor is a glycoprotein that plays a part in hemostasis. It is synthesized in endothelial cells and megakaryocytes. After transcription and translation, pro-vWF is covalently linked to form dimers in the endoplasmic reticulum, and subsequently, large dimers form in the Golgi complex and secretory granules. The pro-von Willebrand factor propeptide then undergoes cleavage, and then both the propeptide and mature von Willebrand factor are secreted into the vessel lumen. It functions as a carrier for factor VIII to maintain its levels and help in platelet adhesion and binding to endothelial components after a vascular injury. Any qualitative or quantitative deficiency of pro-von Willebrand factor will lead to an increased bleeding tendency, and this syndrome is called Von Willebrand disease.

• #2 Pathophysiology of von Willebrand disease – UpToDate

  https://www.uptodate.com/contents/pathophysiology-of-von-willebrand-disease

  Pathophysiology of von Willebrand disease […] von Willebrand disease (VWD) is characterized by quantitative or qualitative abnormalities of von Willebrand factor (VWF), a crucial protein in hemostasis. Heritable VWD can be caused by pathogenic variants in the VWF gene, which lead to an impairment in the synthesis, secretion, clearance, or function of VWF. Acquired von Willebrand syndrome (AVWS) can be caused by several conditions that affect VWF levels and activity. […] The pathophysiology of VWD and AVWS will be reviewed here.

• #3 Von Willebrand Disease: An Overview

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3224412/

  Most commonly inherited bleeding disorder, first described in Aland Islands by Erik von Willebrand. It occurs as a result of decrease in plasma levels or defect in von Willebrand factor which is a large multimeric glycoprotein. […] The pathophysiology of each type depends on the qualitative or quantitative defects in von Willebrand factor. […] VWF is active only in high blood flow condition and shear stress. Hence the organs with extensive small vessels such as skin, uterus, and gastrointestinal tract show deficiency of the factor. The pathophysiology of different forms of VWD can be given as followed. […] Type 1: It is a partial quantitative defect but the clotting impairment may not be seen clearly. Genetic changes in VWF are common in severe cases whereas in milder cases of type 1 VWD, complex spectrum of molecular pathology together with polymorphisms of VWF gene may be seen.

• #4 von Willebrand disease | eClinpath

  https://eclinpath.com/hemostasis/disorders/von-willebrands-disease/

  Von Willebrand disease (vWD) is the most common inherited disorder of hemostasis in both humans and dogs. It is due to a deficiency or abnormality in von Willebrand factor (vWf). […] Von Willebrand factor is produced as a single protein chain (called a monomer), which then dimerizes within the cytoplasm of the megakaryocyte or endothelial cell. Therefore, the smallest component of vWf is a dimer. The dimer spontaneously forms long chains or polymers called multimers, which are held together by disulfide bonds. These multimers impart a very high molecular weight on vWf. The multimeric structure of vWf is important as the higher molecular weight multimers are more effective in hemostasis, so a relative deficiency of these multimers (which occurs in type II vWD) produces more severe bleeding.

• #5 Von Willebrand Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459222/

  Von Willebrand factor is a multimer formed from a basic dimer subunit. It is produced in megakaryocytes and endothelial cells. The size of the multimer determines the physiological hemostatic effect. Bigger multimers are more active and even prothrombic. They are cleaved by circulating proteases into smaller units. These larger multimers are stored in cytoplasmic granules and released in response to a trigger such as thrombin, fibrin, and histamine. […] Larger multimers have more available sites for binding to platelets and endothelium. Von Willebrand factor increases factor VIII half-life by preventing its degradation. […] Of note, von Willebrand factor levels of less than 30% are required for a diagnosis of Von Willebrand disease. Conversely, type III is characterized by a significant decrease in the parameters above.

• #6 Mechanism of Action, Hemostasis and Stages of Hemostasis | HUMATE-P

  https://www.humate-p.com/hcp/about-humate-p/mechanism-of-action

  The size of VWF multimers directly correlates with their in vitro function. […] High molecular weight (HMW) VWF multimers are more effective in supporting primary homeostasis, whereas low molecular weight (LMW) multimers are less functionally active. […] HMW-VWF multimers have been shown to be associated with increased hemostatic activity. […] HMW-VWF multimers are associated with shortened bleeding time. […] People with von Willebrand disease (VWD) have an insufficient amount of VWF protein in the blood, or VWF that is defective. Because VWF is essential in primary hemostasis, an insufficient amount or a supply of defective VWF interferes with proper platelet adherence or aggregation. […] The mainstay of VWD treatment is the replacement of the deficient VWF protein. This results in shortened bleeding time and correction of the coagulation abnormality.

• #7 von Willebrand disease | eClinpath

  https://eclinpath.com/hemostasis/disorders/von-willebrands-disease/

  For vWf, the control mechanism is an enzyme called ADAMTS13 (a disintegrin-like and metalloproteinase domain with thrombospondin type-1 motif, #13), which cleaves vWf, breaking it down into smaller molecular weight multimers. […] Von Willebrand factor has an essential role in primary hemostasis, being important for initiating platelet adhesion to the subendothelium in vessels with high shear rates. […] The multimeric nature of vWf is important in this capturing effect (think of the unfurled protein as a string upon which platelets can transiently bind and roll), whereas compact vWf cannot facilitate initial adhesion to the same extent, presenting far fewer binding sites to platelet receptors. […] vWf mediates platelet adhesion by acting as a bridge between the platelet glycoprotein Ib-IX-V receptor and subendothelial collagen or elastin microfibrils.

• #8 von Willebrand Disease: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206996-overview

  Von Willebrand disease (vWD) is a common, inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of the protein termed von Willebrand factor (vWF). In vWD, defective vWF interaction between platelets and the vessel wall impairs primary hemostasis. […] vWF, a large, multimeric glycoprotein, circulates in blood plasma at concentrations of approximately 10 mg/mL. In response to numerous stimuli, vWF is released from storage granules in platelets and endothelial cells. It performs two major roles in hemostasis. First, it mediates the adhesion of platelets to sites of vascular injury. Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII). […] vWD type 2 is further divided into four variants (2A, 2B, 2N, 2M), based on characteristics of dysfunctional vWF. These categories correspond to distinct molecular mechanisms, with corresponding clinical features and therapeutic recommendations.

• #9 Von Willebrand disease – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/von-willebrand-disease/

  Von Willebrand disease (vWD) is a bleeding disorder characterized by a deficiency or dysfunction of von Willebrand factor (vWF). […] In the vast majority of cases, vWD is an inherited disorder caused by mutations in the vWF gene. vWF is involved in platelet adhesion and prevents degradation of factor VIII. Therefore, vWF deficiency or dysfunction impairs primary hemostasis as well as the intrinsic pathway of secondary hemostasis. […] Deficiency or dysfunction of vWF leads to: […] Dysfunctional platelet adhesion impaired primary hemostasis […] Reduced binding of factor VIII increased degradation factor VIII activity impaired intrinsic pathway of secondary hemostasis.

• #10 About Von Willebrand Disease (VWD) | VONVENDI®

  https://www.vonvendipro.com/about-vwd

  The underlying cause of von Willebrand disease (VWD) is a deficiency or defect in von Willebrand factor (VWF), a multimeric protein important for clotting. […] VWF is critical for hemostasis and thrombus formation and plays 2 key roles: Binding to collagen and platelets to facilitate platelet plug formation. […] Binding to factor VIII (FVIII) to protect it from clearance and stabilize plasma FVIII levels. […] Because VWF protects FVIII in plasma, VWF deficiency or defect leads to increased FVIII clearance, resulting in low FVIII levels in some patients with VWD. […] An important fact to note about all 3 types of VWD is that they only impact production of functional VWF; VWD itself does not impact patients’ ability to produce FVIII. […] Because VWD patients lack VWF multimer protein, an important protein for clotting, they are prone to bleeds.

• #11 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Von-Willebrand-Disease-Pathophysiology.aspx

  The condition known as von Willebrand disease (vWD) is the result of a reduction in the plasma levels of, or the production of a defective form of, the coagulation factor known as von Willebrand factor (vWF). This is a large glycoprotein made up of many monomers. […] Since vWF is activated only under conditions of high blood flow and shear stress, organs that have many small vessels, and therefore typically have a slow blood flow, do not have adequate levels of this factor. […] Genetically, vWF is altered such that the level of the factor is low. In the dominant severe type 1 vWD, genetic mutations interfere with the intracellular transport of the subunits of this glycoprotein. […] Another mechanism is the rapid clearance of the factor from the plasma, leading to a shorter cleavage time of the multimer in circulation by ADAMTS-13. As a result, the distribution pattern of the multimer changes, which leads to a fall in vWF activity.

• #12 von Willebrand disease – Wikipedia

  https://en.wikipedia.org/wiki/Von_Willebrand_disease

  Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. […] Von Willebrand factor is mainly active in conditions of high blood flow and shear stress. Deficiency of VWF, therefore, shows primarily in organs with extensive small vessels, such as skin, gastrointestinal tract, and uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly. […] In more severe cases of type 1 VWD, genetic changes are common within the VWF gene and are highly penetrant. In milder cases of type 1 VWD, a complex spectrum of molecular pathology may exist in addition to polymorphisms of the VWF gene alone.

• #13 Von Willebrand disease pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Von_Willebrand_disease_pathophysiology

  Von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor. […] Von Willebrand’s Disease can also be acquired secondary to another diseases. Acquired VWD is associated with other diseases resulting from different pathological processes. These pathological processes include Antibody formation resulting in Impaired vWF function and Increased clearance of VWF. Other mechanisms are enhanced proteolysis and decreased synthesis of von Willebrand factor (vWF). […] Pathogenetic mechanisms of inherited VWD include mutations affecting VWF trafficking, storage, secretion, and clearance. […] Pathogenetic mechanisms of acquired VWD include antibody formation resulting in impaired vWF function and increased clearance of VWF.

• #14 von Willebrand Disease: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206996-overview

  vWD type I causes a mild to moderate quantitative deficiency of vWF (ie, about 20-50% of normal levels). In individuals with vWF levels 0.3 IU/mL, type I is usually inherited in autosomal dominant fashion; in those with levels 0.3 IU/mL, mutations show variable penetrance. […] vWD type II is due to qualitative vWF abnormalities and is subdivided into types IIA, IIB, IIN, and IIM. vWD type IIA, the most common qualitative abnormality of vWF, is associated with selective loss of large and medium-sized multimers. Most cases have autosomal dominant inheritance. […] vWD type IIB characterized by the loss of large multimers occurs through a mechanism distinct from that of type IIA. Observations to date have identified a critical region of vWF involved in the binding of vWF to the platelet receptor glycoprotein Ib (GpIb). Each of the identified single amino acid substitutions is thought to result in a gain of function, leading to spontaneous binding of vWF to platelets.

• #15 Von Willebrand Disease: An Overview

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3224412/

  Type 2: It is a qualitative defect where there is no change in plasma VWF levels but characterized by a structural and functional defects based on which, it is further sub-divided into four types. […] Type 2A: It is characterized by a decreased VWF mediated platelet adhesion. This is usually because of deficiency of high molecular weight multimers in the circulation. […] Type 2B: It is characterized by a decreased level of large multimers in the plasma and a markedly increased proteolysis. […] Type 2M: It includes qualitative variants in which VWF dependant platelet adhesion is decreased without any deficiency of high molecular weight VWF multimers. […] Type 2N: In this, the variants have a marked decline in the binding affinity for factor VIII. […] Type 3: It is caused by recessive mutation which leads to undetectable VWF level. Hence it is often termed as a severe form. […] Acquired VWD: In this, the function of VWF is not inherited but its antibody complex is rapidly cleared from the circulation. It has a diverse pathology.

• #16 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Von-Willebrand-Disease-Pathophysiology.aspx

  In type 2 vWD, the plasma vWF level is normal but is structurally and functionally defective. The type of defect is the basis for further subclassification. […] Type 2A vWD causes decreased platelet adhesion that is mediated by a deficiency of high molecular weight vWF multimers in circulation. This reduction may be due to either a defect in the assembly of the multimers or an increase in the rate of multimer cleavage. […] In type 2 vWD, large multimers are markedly reduced in circulation, while the rate of catabolism is high. This is due to a mutation that allows normal multimerization to occur in the Golgi apparatus but results in the binding of the secreted multimers to the platelets where they are cleaved by ADAMTS-3. […] This causes failure of effective platelet adhesion by the abnormally small multimers, with subsequent failure to bind to connective tissue.

• #17

  https://omim.org/entry/613554

  Von Willebrand disease type 2 is caused by mutation in the gene encoding von Willebrand factor (VWF; 613160), which maps to chromosome 12p13. […] Von Willebrand disease type 2, which is divided in subtypes 2A, 2B, 2M, and 2N, is characterized by qualitative abnormalities of the VWF protein. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8. […] The mutant VWF protein in von Willebrand disease type 2A has decreased platelet adhesion due to a selective deficiency of high molecular weight multimers. The decrease in large multimers can be due to (1) a failure to synthesize the multimers (’group 1′) or (2) enhanced ADAMTS13 (604134)-mediated proteolysis of the secreted high molecular weight protein (’group 2′). Regardless of mechanism in type 2A, the loss of large multimers is associated with decreased VWF-platelet interactions and/or decreased VWF-connective tissue interactions.

• #18 von Willebrand Disease: Practice Essentials, Etiology, Epidemiology

  https://emedicine.medscape.com/article/206996-overview

  In vWD type IIB, the mutant vWF spontaneously binds to GpIb in the absence of subendothelial contact. The large multimers have the highest affinity for GpIb and are rapidly cleared from the plasma along with the bound platelets, resulting in thrombocytopenia and the characteristic loss of large multimers. […] vWD type IIN, sometimes referred to as vWD Normandy, is characterized by a defect residing within the patient’s plasma vWF that interferes with its ability to bind FVIII. This has important implications in the differential diagnosis of hemophilia. […] vWD type III, a severe, quantitative deficiency associated with very little or no detectable plasma or platelet vWF, has a profound bleeding disorder. vWD type III appears to result from the inheritance of a mutant vWF gene from both parents.

• #19

  https://omim.org/entry/613554

  The mutant VWF protein in VWD type 2B shows increased affinity to platelet GP1BA (606672), resulting in increased platelet aggregation, and increased proteolysis of VWF subunits causing a decrease of large VWF multimers. […] The mutant VWF protein in VWD type 2M shows decreased platelet adhesion without a deficiency of high molecular weight multimers. This functional defect is caused by mutations that disrupt VWF binding to platelets or to subendothelium, consistent with a loss of function. […] The mutant VWF protein in VWD type 2N shows markedly decreased binding affinity for factor VIII, and this may be confused with mild hemophilia A (306700). […] Riddell et al. (2009) proposed a new subtype of VWF characterized by clinically significant bleeding episodes due to a mutant VWF protein with defective collagen binding, termed 'VWF 2CB.’

• #20 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Von-Willebrand-Disease-Pathophysiology.aspx

  In type 2M vWD, vWF-dependent platelet adhesion is reduced, despite a normal level of high molecular weight multimers in plasma. This is due to normal secretion and assembly of multimers, but a mutation-dependent loss of function that prevents the normal binding of vWF to the platelets. […] This inability of vWF to bind to platelets exposes less of the multimer to the cleaving enzyme ADAMTS-13, which leads to the persistence of large multimers in distribution that is almost identical to that when they were originally secreted by endothelial cells. […] Type 2N vWD is characterized by a very low binding affinity of vWF for factor VIII. Both homozygous and heterozygous mutations responsible for this defect have been recognized. […] The failure to bind factor VIII leads to its rapid catabolism, thereby causing plasma levels of factor VIII to be very low. […] Type 3 vWD form is caused by a recessive mutation which results in an almost total absence of vWF, which is why this type is often termed severe vWD. […] Acquired vWD is due to the rapid clearance of vWF from the plasma after it forms a complex with its antibody.

• #21 Von Willebrand Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459222/

  A qualitative decrease with specific variations characterizes type II disease: […] Type 2A: variable decrease in von Willebrand factor Ag and VIII:C with a significant decrease in von Willebrand factor activity and absence of large and intermediate size multimers. […] Type 2B: variable decrease in von Willebrand factor Ag and VIII:C and a significant decrease in von Willebrand factor activity and absence of large multimers. However, most importantly, this type is hypersensitive to ristocetin-induced platelet aggregation (RIPA). […] Type M: vWF activity is decreased relative to Ag and multimers are present. […] Type N: this is characterized variably by a decrease in vWF Ag and activity but is distinguished from the other types by the significant decrease in VIII: C, albeit usually more than 5%. This specific subtype can be confused with hemophilia A.

• #22 Orphanet: Acquired von Willebrand syndrome

  https://www.orpha.net/en/disease/detail/99147

  A rare bleeding disorder characterized by defects in von Willebrand factor, similar to those seen in hereditary von Willebrand disease (VWD), but which are caused by an underlying pathology, generally in elderly patients without any personal or family history of bleeding anomalies. […] Three principle pathogenic mechanisms have been described: 1) the presence of autoantibodies (inhibiting or noninhibiting) that form immune complexes with the von Willebrand factor (VWF) leading to rapid clearance of VWF from the circulation (the mechanism most commonly implicated in AVWS associated with monoclonal gammopathies and autoimmune diseases); 2) absorption of VWF onto malignant cell clones (the mechanism implicated in AVWS associated with neoplasia); 3) increased proteolysis of high molecular weight VWF multimers under abnormal hemorheologic conditions caused by cardiovascular malformations (such as aortic valve stenosis) or mechanical circulatory devices (such as ventricular assist devices or extracorporeal membrane oxygenation). Monoclonal gammopathy of undetermined significance (MGUS) is the most common underlying condition associated with AVWS. […] The long-term prognosis mainly depends on the underlying pathology associated with the disease. The short- and mid-term prognosis may be dependent on the severity of acute bleeding events.

• #23

  https://haematologica.org/article/view/9977

  In cases associated with plasma cell dyscrasias (MGUS and multiple myeloma), as well as in autoimmune diseases such as systemic lupus erythematosus, circulating autoantibodies directed against functional or non-functional vWF domains have been reported. […] Antibody binding to vWF leads to the formation of immune complexes that are cleared from the circulation by the reticulo-endothelial system. […] A mechanism involving the selective adsorption of HMW multimers on tumor cells leading to their enhanced plasma clearance has been described in lymphoproliferative diseases (multiple myeloma, Waldenstrms macroglobulinemia, non-Hodgkin lymphoma, hairy cell leukemia) and solid cancers. […] In MGUS, the aberrant expression on abnormal plasma cells of the glycoprotein Ib (the principal platelet receptor of vWF) was associated with its selective binding to these cells. […] vWF adsorption onto the cell membranes and subsequent plasma clearance has also been involved in AvWS associated with myeloproliferative neoplasms.

• #24 The Role of Cardiovascular Diseases in the Pathogenesis of Acquired von Willebrand Syndrome – Hematology Advisor

  https://www.hematologyadvisor.com/features/role-cardiovascular-diseases-pathogenesis-acquired-von-willebrand-syndrome/

  High shear stress in blood vessels due to cardiovascular disease may be associated with the development of acquired von Willebrand syndrome. […] Various autoimmune diseases, hypothyroidism, and certain cardiovascular conditions causing nonphysiological high shear stress in blood vessels are known sources of AVWS. Although many bleeding disorders are attributable to genetic mutations, AVWS results from excessive cleavage of VWF multimers, which have essential functions in platelet aggregation and hemostasis. Ultimately, excessive cleavage leads to a major reduction in high molecular weight multimers, resulting in the clinical bleeding phenotype. […] It is conceivable that the disease [AVWS] causes angiodysplasia, possibly through impaired perfusion of blood, reduced pulse pressure, or a decrease of high molecular weight multimers, the reviewers noted.

• #25

  https://haematologica.org/article/view/9977

  In the past, AvWS was considered a very rare hemorrhagic disease. The more recent discovery of its association with relatively frequent cardiovascular disorders suggests that its prevalence is higher than previously thought. […] The complex pathophysiology of AvWS involves various and different mechanisms. Most cases are due to an increased plasma clearance of vWF caused by such mechanisms as antibodies, cell adsorption, shear stress or increased proteolysis. […] In cardiac valvulopathies and left ventricular assist devices, sheering of high-molecular-weight (HMW) vWF multimers by mechanical stress or proteolysis induced by ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) are involved. […] In patients with hypothyroidism, the syndrome is caused by the decreased synthesis of an otherwise qualitatively normal vWF, and this can be reversed by l-thyroxine therapy.

• #26 von Willebrand disease – Wikipedia

  https://en.wikipedia.org/wiki/Von_Willebrand_disease

  The individual’s ABO blood group can influence presentation and pathology of VWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group-specific VWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I VWD, and some individuals of blood group AB with a genetic defect of VWF may have the diagnosis overlooked because VWF levels are elevated due to blood group.

• #27

  https://haematologica.org/article/view/haematol.2024.285244

  Bleeding in the gastrointestinal tract in patients with von Willebrand disease continues to pose a therapeutic challenge for clinicians. […] Defective angiogenesis in the gut is primarily responsible, resulting in angiodysplastic malformations making bleeding notoriously refractory to standard replacement therapy. […] A substantial body of evidence now shows that von Willebrand factor has a role in the regulation of angiogenesis but the mechanisms responsible for the formation of vascular malformations remain incompletely understood. […] This is a narrative review linking VWF to angiodysplasia, the associated molecular mechanisms and the implications for therapy. […] Defective angiogenesis in the gut may give rise to vascular malformations (angiodysplasia) that are responsible for a bleeding tendency which is frequently refractory to replacement therapy and represents the principal unsolved therapeutic problem in VWD today.

• #28

  https://haematologica.org/article/view/haematol.2024.285244

  The first mechanistic link between VWF and defective angiogenesis was provided by Starke et al. in 2011, who showed that inhibition of VWF expression in human umbilical vein endothelial cells led to increased proliferation, migration and angiogenesis. […] Evidence that VWF plays an important role in vascular development and angiogenesis is apparent, but the mechanisms by which it regulates angiogenesis and the reason for dependency on HMWM remain unclear. […] Loss of VWF leads to increased Angpt2 release from endothelial cells; increased Angpt2 signaling (depending on context) promotes angiogenesis by synergizing with VEGF signaling; increased Angpt2 likely mimics and/or accentuates inflammaging in the gut. […] The effects of VWF on angiogenesis are at least partly dependent on HMWM.

• #29 von Willebrand factor links primary hemostasis to innate immunity | Nature Communications

  https://www.nature.com/articles/s41467-022-33796-7

  The plasma multimeric glycoprotein von Willebrand factor (VWF) plays a critical role in primary hemostasis by tethering platelets to exposed collagen at sites of vascular injury. […] However, the molecular mechanisms through which VWF exerts its immuno-modulatory effects remain poorly understood. In this study, we report that VWF binding to macrophages triggers downstream MAP kinase signaling, NF-B activation and production of pro-inflammatory cytokines and chemokines. […] Cumulatively, our findings define an important biological role for VWF in modulating macrophage function, and thereby establish a novel link between primary hemostasis and innate immunity. […] Importantly, data from studies conducted in a number of different animal inflammatory disease models suggest that VWF does not merely serve as a marker of acute EC activation, but rather that it plays an active role in mediating the underlying pathophysiology.

• #30 von Willebrand factor links primary hemostasis to innate immunity | Nature Communications

  https://www.nature.com/articles/s41467-022-33796-7

  Thus, our data highlight that VWF not only plays a key role in initiating primary hemostasis and platelet plug formation at the site of blood vessel injury, but also that it can plays a role in innate immunity by priming macrophages in the vicinity to promote a pro-inflammatory response. […] Our data further demonstrate that MAPKinase p38 is involved in the activation of rapid HIF-1 dependent glycolysis following VWF treatment. […] Collectively, these findings support the hypothesis that VWF plays a role in modulating macrophage recruitment into atheromatous plaques.

• #31 Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module | Nature Communications

  https://www.nature.com/articles/s41467-021-22634-x

  Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. […] Understanding the mechano-activation mechanism of VWF is key to elucidate the pathophysiology of thrombotic diseases and to develop safe anti-thrombotic therapeutics. […] All reported type 2B mutations are located in the A1 domain or the flanking regions around A1, suggesting that autoinhibitory elements are localized around A1. […] Our recent characterization of A1 fragments with differential affinities for GPIb suggests that both N- and C-terminal flanking sequences cooperatively provide hydrogen-deuterium exchange protection on many residues in A1, particularly the 32 loop as a part of the GPIb-binding site, and thus may constitute an autoinhibitory module (AIM).

• #32 Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module | Nature Communications

  https://www.nature.com/articles/s41467-021-22634-x

  Here, we report that the discontinuous AIM does resist tensile force, and cooperatively unfolds above a certain threshold of force to expose A1. […] We provide additional evidence that links disruption of the AIM with an increase of the A1 affinity for GPIb under pathologically relevant conditions. […] Overall, these results indicate that H1268D and R1341Q activate A1 by destabilizing or disrupting the AIM, and suggest that other type 2B VWD mutations could activate A1 in a similar manner. […] These results suggest that widely documented factors of VWF activation, such as shear force, type 2B VWD mutations, and ristocetin, may share a common molecular mechanism—by destabilizing or disrupting the AIM and its shielding of the A1 domain.

• #33 von Willebrand factor – Wikipedia

  https://en.wikipedia.org/wiki/Von_Willebrand_factor

  Von Willebrand Factor’s primary function is binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites. […] VWF plays a major role in blood coagulation. Therefore, VWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that VWF uncoils under these circumstances, decelerating passing platelets. […] Hereditary or acquired defects of VWF lead to von Willebrand disease (vWD), a bleeding diathesis of the skin and mucous membranes, causing nosebleeds, menorrhagia, and gastrointestinal bleeding. The point at which the mutation occurs determines the severity of the bleeding diathesis. […] In thrombotic thrombocytopenic purpura (TTP) and hemolyticuremic syndrome (HUS), ADAMTS13 either is deficient or has been inhibited by antibodies directed at the enzyme. This leads to decreased breakdown of the ultra-large multimers of VWF and microangiopathic hemolytic anemia with deposition of fibrin and platelets in small vessels, and capillary necrosis. […] Higher levels of VWF are more common among people that have had ischemic stroke (from blood-clotting) for the first time. […] VWF is a marker of endothelial dysfunction, and is consistently elevated in atrial fibrillation, associated with adverse outcomes.

• #34 Von Willebrand Disease (VWD) | Symptoms & Treatments | NBDF

  https://www.bleeding.org/bleeding-disorders-a-z/types/von-willebrand-disease

  Von Willebrand disease (VWD) is an inheritable bleeding disorder. Many different proteins are needed to make a persons blood clot successfully. People with VWD are either missing or low in the clotting protein von Willebrand factor (VWF) or it doesnt work as its supposed to. For a person to make a successful clot, VWF binds to factor VIII (8), another clotting protein, and platelets in blood vessel walls. This process will help form a platelet plug during the clotting process. People with VWD are not able to form this platelet plug, or it will take longer to form. […] People with type 2 VWD have a normal levels of VWF, but the factor doesnt function as it should. Type 2 is broken down into four subtypes: type 2A, type 2B, type 2M and type 2N, depending on the specific way the VWF is defective. […] People with type 3 VWD have a very low levels or no VWF in their blood. Some people with this type of VWD may also be low in factor VIII (factor eight). Symptoms are typically severe, and include spontaneous bleeding episodes, often into their joints and muscles.

• #35 Von Willebrand Disease – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/thrombocytopenia-and-platelet-dysfunction/von-willebrand-disease

  Diagnosis requires measuring total plasma VWF antigen, VWF function as determined by the ability of plasma to support agglutination of normal platelets by ristocetin (ristocetin cofactor activity), and the plasma factor VIII level. […] Type 2 subtypes are suspected if test results are discordant, ie, VWF antigen is higher than expected for the degree of abnormality in ristocetin cofactor activity. […] For patients with type 2 VWD, those with type 3 VWD, or those with type 1 VWD who are undergoing more extensive invasive procedures, treatment involves replacement of VWF by infusion of intermediate-purity factor VIII concentrates, which contain components of VWF. […] Desmopressin, an analog of vasopressin (antidiuretic hormone) that stimulates release of VWF into the plasma and may increase levels of factor VIII, can be helpful. […] For women with heavy menstrual bleeding due to VWD, a brief period of treatment with tranexamic acid by mouth or intranasal desmopressin may decrease bleeding.

• #36 Pathophysiology of von Willebrand disease – UpToDate

  https://www.uptodate.com/contents/classification-and-pathophysiology-of-von-willebrand-disease

  von Willebrand disease (VWD) is characterized by quantitative or qualitative abnormalities of von Willebrand factor (VWF), a crucial protein in hemostasis. Heritable VWD can be caused by pathogenic variants in the VWF gene, which lead to an impairment in the synthesis, secretion, clearance, or function of VWF. […] The pathophysiology of VWD and AVWS will be reviewed here.

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