150-kD von Willebrand factor binding protein extracted from human vascular subendothelium is type VI collagen.

Rand, Jacob H.; Patel, Nilesh; Schwartz, Ernest; Zhou, Shengli; Potter, Barry J.

doi:10.1172/jci115285

Cited by 110 publications

(59 citation statements)

References 48 publications

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“…VWF BINDING TO COLLAGENS VWF binds specifically to several collagens in vitro, including types I, II, III, IV, V, and VI, but it does not bind denatured gelatin (55)(56)(57). Immobilized fibrillar collagens (e.g.…”

Section: Platelet Adhesion To Connective Tissuementioning

confidence: 99%

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Biochemistry and Genetics of Von Willebrand Factor

Sadler

1998

Annu. Rev. Biochem.

1,249

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Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical ≈250 kDa subunits into disulfide-linked multimers that may be >20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clincial symptoms and the response to therapy. CONTENTS

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Section: Platelet Adhesion To Connective Tissuementioning

confidence: 99%

“…These findings have focused attention on other candidates. For example, the nonfibrillar collagen type VI binds VWF (57) and is resistant to collagenase (61) or α,α -dipyridyl (62). VWF also appears to colocalize with collagen type VI but not fibrillar collagens in subendothelial matrix (63).…”

Section: Platelet Adhesion To Connective Tissuementioning

confidence: 99%

Biochemistry and Genetics of Von Willebrand Factor

Sadler

1998

Annu. Rev. Biochem.

1,249

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“…Type IV and type VI collagen also bind VWF, but via the A1 domain 43. The sequence variant p.Arg1399His within the A1 domain prevents VWF from binding type IV and VI collagen44 and has been reported to occur in up to 2% of the Caucasian population 45.…”

Section: Clinical Evaluation Of Vwf Collagen Bindingmentioning

confidence: 99%

Current issues in diagnosis and treatment of von Willebrand disease

Keesler

Flood

2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Classification of VWD includes quantitative (types 1 and 3) and qualitative (type 2) variants.New assays of VWF‐platelet binding may improve accuracy in diagnosis.Collagen binding represents an additional function of VWF not measured by current tests.Treatment options for VWD include desmopressin, plasma‐derived, and recombinant VWF. Clinically, von Willebrand disease (VWD) presents as mucosal bleeding caused by a decreased quantity or quality of von Willebrand factor (VWF). Diagnosis of VWD requires careful consideration of patient specific factors, bleeding symptoms, and laboratory results. Patients with borderline low VWF levels remain challenging, given that low VWF is not necessarily a guarantee of bleeding, but is present in many patients with symptoms, and treatment of low VWF may improve bleeding. Laboratory diagnosis of VWD is complex and no single test can determine the presence or absence of functional VWF. Historically, VWF binding to platelet GPIbα was measured by the ristocetin cofactor assay (VWF:RCo); a new assay using platelet GPIbα in the absence of ristocetin (VWF:GPIbM) is gradually replacing the VWF:RCo due to improved accuracy in diagnosis. VWF binding to collagen is a separate function, and requires specific testing to determine if a collagen binding defect is present. Regardless of these laboratory complexities, clinicians can empirically treat VWD to alleviate bleeding symptoms by raising VWF levels through desmopressin or VWF concentrate. Recombinant VWF is now available, but clinicians may need to add an initial dose of FVIII when treating emergency bleeds.

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“…The latter is one of the first hemostatic events following endothelial disruption and occurs through the specific binding of VWF to exposed subendothelial matrix proteins (principally collagen). 3 Once immobilized, VWF affinity for the glycoprotein (GP) Ib-IX-V receptor complex on the surface of circulating platelets is significantly enhanced. 4 This results in the tethering of platelets at sites of vascular damage and in the formation of a primary platelet plug.…”

Section: Introductionmentioning

confidence: 99%

Proteolytic inactivation of ADAMTS13 by thrombin and plasmin

Crawley

Lam

Rance

et al. 2005

Blood

212

193

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The multimeric size and the function of circulating von Willebrand factor are modulated via its proteolytic cleavage by the plasma metalloproteinase, AD-AMTS13. It is unclear how ADAMTS13 activity is regulated within the vascular system. In the absence of a regulatory mechanism, ADAMTS13 activity might compromise platelet adhesion at sites of vascular injury. We hypothesized that at sites of vascular injury, ADAMTS13 activity could be regulated locally by coagulation proteinases. Initiation of coagulation in human plasma resulted in the disappearance of added full-length recombinant ADAMTS13. This loss was inhibited by hirudin. Using purified proteins, we showed that ADAMTS13 is proteolyzed at several cleavage sites by thrombin in a time-and concentration-dependent manner. Furthermore, this proteolysis ablated ADAMTS13 activity against purified von Willebrand factor. Preincubation of thrombin with soluble thrombomodulin, but not heparin, inhibited the proteolysis of AD-AMTS13, suggesting the involvement of IntroductionVon Willebrand factor (VWF) is a large (2050 amino acid/ϳ250 kDa) multidomain glycoprotein whose functions are critical for normal hemostasis. 1 VWF has 2 principal roles that influence the hemostatic process: (1) it acts as a carrier protein for coagulation factor VIII 2 and (2) it mediates rapid adhesion of platelets to sites of vascular perturbation. The latter is one of the first hemostatic events following endothelial disruption and occurs through the specific binding of VWF to exposed subendothelial matrix proteins (principally collagen). 3 Once immobilized, VWF affinity for the glycoprotein (GP) Ib-IX-V receptor complex on the surface of circulating platelets is significantly enhanced. 4 This results in the tethering of platelets at sites of vascular damage and in the formation of a primary platelet plug. Tethered platelets are subsequently activated and expose phosphatidylserine-rich surfaces that are critical for efficient thrombin generation to occur. 5 VWF is constitutively secreted into the blood by endothelial cells as multimers of varying size that differ predominantly in the number of component VWF units. A significant proportion is also stored within Weibel-Palade bodies, predominantly as "ultra-large" multimers (UL-VWF) 6 that may exceed 2 ϫ 10 4 kDa. 1 This pool is released on demand in response to endothelial cell activation. 7 The properties of circulating VWF are, in part, dependent on its molecular size. Larger VWF multimers not only bind circulating platelets more readily than smaller forms, but also undergo marked conformational changes in response to the rheologic forces exerted by the circulating blood. 8 Under normal flowing conditions, VWF multimers circulate in a globular form. However, when VWF is exposed to increased shear forces, these molecules unravel into a "stringlike" conformation. This increases the number of exposed platelet/matrix binding sites and thus enhances the platelet tethering potential of the VWF molecule.Thrombotic thrombocytopenic purpura (TTP) is...

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150-kD von Willebrand factor binding protein extracted from human vascular subendothelium is type VI collagen.

Abstract: We have previously shown that von

Cited by 110 publications

References 48 publications

Biochemistry and Genetics of Von Willebrand Factor

Biochemistry and Genetics of Von Willebrand Factor

Current issues in diagnosis and treatment of von Willebrand disease

Proteolytic inactivation of ADAMTS13 by thrombin and plasmin

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