Nature of von Willebrand Factor: A New Assay and a Specific Inhibitor

Sarji, Kay E.; Stratton, Robert D.; Wagner, Robert H.; Brinkhous, K. M.

doi:10.1073/pnas.71.8.2937

Cited by 63 publications

(33 citation statements)

References 14 publications

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“…In 1974, Sarji et al first reported a case of an alloantibody against VWF in a multitransfused patient. 6 This was followed quickly by additional reports from Sweden and Italy, including the description of a precipitating anti-VWF antibody by Mannucci et al [7][8][9] In such cases, treatment with VWF concentrates is rendered ineffective, and anaphylaxis with subsequent exposures has been described. 10,11 In this review, we will discuss the epidemiology of alloantibodies against VWF including what is known about underlying risk factors, the challenges facing laboratory characterization, and the clinical presentation and treatment options.…”

Section: Introductionmentioning

confidence: 99%

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Alloantibodies in von Willebrand disease

James¹,

Lillicrap

Mannucci

2013

Blood

100

109

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The development of alloantibodies against von Willebrand factor (VWF) represents a rare but serious complication of treatment of von Willebrand disease (VWD), occurring in ∼5% to 10% of type 3 VWD patients. Affected patients can present with a range of symptoms, including lack or loss of hemostatic response to infused VWF concentrates up to anaphylactic reactions in rare cases. It is classically reported in multitransfused patients and occurs most frequently in patients with partial or complete VWF gene deletions. A positive family history of anti-VWF antibodies also appears to be a risk factor. There is a lack of standardization of laboratory methods for antibody identification and characterization. Issues of variability in laboratory approaches as well as the rarity of the complication act as a barrier to future studies. Recombinant factor VIII as well as bypassing agents and immune tolerance have been reported as effective treatments; however, aside from case reports, little exists in the literature to guide management. The imminent clinical availability of recombinant VWF has prompted a resurgence of interest in this area. Additional study is warranted to address the deficiencies in our understanding of this treatment complication.

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Section: Introductionmentioning

confidence: 99%

“…Interactions with plasma FVIII are possible, but likely as a result of the bound antibody causing steric hindrance of the FVIII binding site on VWF. 6,7,40 This distinction is clinically relevant in terms of treatment options for patients with anti-VWF antibodies.…”

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confidence: 99%

Alloantibodies in von Willebrand disease

James¹,

Lillicrap

Mannucci

2013

Blood

100

109

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“…The carrier protein eluted in the void volume while the small active subunit containing the procoagulant (PC)' activity eluted later. The observation that both purified Factor VIII and the void volume protein from the salt dissociation studies corrected the platelet defect in von Willebrand's disease led to the suggestion that the carrier protein contained the von Willebrand factor (vWF) activity (13)(14)(15)(16)(17)(18)(19)(20). These studies have been hampered by an absence of criteria of purity and the lack of biochemical characterizations of the protein(s) associated with the PC or vWF activities.…”

Section: Introductionmentioning

confidence: 99%

“…Several investigators (9)(10)(11)(12)(13)(14)(15)(16) have recently reported that Factor VIII activity in plasma or plasma concentrates can be dissociated by chromatography in certain high ionic strength buffers, particularly 0.25 M CaCl2, to yield a high molecular weight "carrier protein" and a low molecular weight "active subunit." The carrier protein eluted in the void volume while the small active subunit containing the procoagulant (PC)' activity eluted later.…”

Section: Introductionmentioning

confidence: 99%

Studies on human antihemophilic factor. Evidence for a covalently linked subunit structure.

Switzer¹,

McKee²

1976

J. Clin. Invest.

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A B S T R A C T When purified antihemophilic factor (Factor VIII) was rechromatographed on 4% agarose in 0.15 M NaCl or 1.0 M NaCi, a single protein peak, containing both procoagulant activity and von Willebrand factor activity, as defined by ristocetin-induced platelet aggregation, was eluted in the void volume. Purified Factor VIII immediately lost about 30% of its procoagulant activity when dissolved in 0.25 M CaC12, and when rechromatographed on 4% agarose in 0.25 M CaCl2, the protein peak and von Willebrand factor activity remained coincident in the void volume; however, most of the remaining procoagulant activity was eluted after the void volume. The elution position of Factor VIII procoagulant activity from 4% agarose in 0.25 M CaCl2, and hence its apparent molecular weight, varied with the protein concentration applied to the column; at low protein concentrations it was eluted close to the inner volume. Yet on Sephadex G-200 in 0.25 M CaCl, the protein and procoagulant activity were eluted together in the void volume. These observations suggested that the Factor VIII procoagulant activity was not eluting according to size or shape, but was adsorbing to some extent to the agarose. Isolated activity peak material from the 0.25 M CaCl2 columns contained protein and had a typical ultraviolet spectrum. Even at high concentrations, the protein contained no thrombin, Factors IX, X, or Xa activity, or detectable phospholipid. In addition to Factor VIII procoagulant activity, which could be inactivated by a human antibody to Factor VIII, the activity peak protein also contained von Willebrand factor activity. Like native Factor VIII and the A preliminary report of this work was given at the 47th Scientific Session of the American Heart Association,

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“…FVIII and vWF) might be properties of the same molecule and conceivably of each subunit (10)(11)(12). More recently it has been shown that when the FVIII/vWF protein(s) is rechromatographed on 4% agarose in certain high ionic strength solvents, particularly 0.25 M CaCl2, virtually all of the protein and vWF activity elute in the void volume, but most of the FVIII procoagulant activity elutes much later (13)(14)(15)(16)(17)(18)(19)(20)(21). These observations have led to the development, explicitly or implicitly, of four different hypotheses for the structure-function relationships of the FVIII/vWF Recent evidence from this laboratory was interpreted to support the last model (22,23).…”

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confidence: 99%

Some Effects of Calcium on the Activation of Human Factor VIII/Von Willebrand Factor Protein by Thrombin

Switzer¹,

McKee²

1977

J. Clin. Invest.

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A B S T R A C T When Factor VIII/von Willebrand factor (FVIII/vWF) protein is rechromatographed on 4% agarose in 0.25 M CaCl2, the protein and vWF activity appear in the void volume, but most ofthe FVIII procoagulant activity elutes later. Recent evidence suggests that the delayed FVIII procoagulant activity is a proteolytically modified form of FVIII/vWF protein that filters anomalously from agarose in 0.25 M CaCl2. To test whether or not thrombin is the protease involved, the effect of 0.25 M CaCl2 on FVIII/vWF and its reaction with thrombin was examined. About 30% of the FVIII procoagulant activity was lost immediately when solutions of FVIII/vWF protein were made 0.25 M in CaCl2. When FVIII in 0.15 M NaCl was activated with 0.04 U thrombin/ml and then made 0.25 M in CaCl2, the procoagulant activity of a broad range of FVIII/vWF protein concentrations remained activated for at least 6 h. But, in 0.25 M CaCl2, the increase in FVIII procoagulant activity in response to thrombin was much more gradual and once activated, the procoagulant activity was stabilized by 0.25 M CaCl2. When thrombin-activated FVIII/vWF protein was filtered on 4% agarose in 0.15 M NaCl, there was considerable inactivation of FVIII procoagulant activity; however, the procoagulant activity that did remain eluted in the void volume. In contrast, when thrombin-activated FVIIIVvWF protein was filtered in 0.25 M CaCl2, the FVIII procoagulant activity eluted well after the void volume and remained activated for 6 h.

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Nature of von Willebrand Factor: A New Assay and a Specific Inhibitor

Cited by 63 publications

References 14 publications

Alloantibodies in von Willebrand disease

Alloantibodies in von Willebrand disease

Studies on human antihemophilic factor. Evidence for a covalently linked subunit structure.

Some Effects of Calcium on the Activation of Human Factor VIII/Von Willebrand Factor Protein by Thrombin

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