von Willebrand Factor and Factor VIII Are Independently Required To Form Stable Occlusive Thrombi in Injured Veins.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1789-1789
Author(s):  
Anil K. Chauhan ◽  
Janka Kisucka ◽  
Colin B. Lamb ◽  
Wofgang Bergmeier ◽  
Denisa D. Wagner
Keyword(s):  
Transgenic Mice ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Flow Conditions ◽  
Venous Flow ◽  
Experimental Thrombosis ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand factor (VWF) is a large adhesive glycoprotein synthesized in megakaryocytes and endothelial cells and stored in platelet a-granules and Weibel-Palade bodies respectively. It protects Factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Therefore in order to understand the in vivo role of VWF and FVIII in experimental thrombosis under venous flow conditions, we decided to evaluate thrombosis in VWF−/−, FVIII−/− and transgenic mice lacking the GPIbα extracellular domain which was replaced by human Interleukin-4 receptor (IL4Rα/GPIbα-tg). In ferric chloride-injured veins, platelet adhesion to subendothelium is decreased and thrombus growth is impaired in the VWF−/− mice when compared to wild-type (WT). In the WT mice, thrombi grew to occlusive size with a mean time of 18 min and all injured venules occluded, whereas in VWF−/− mice none of the vessels occluded by 40 min after injury, when observation was terminated. Venules of mice deficient in FVIII treated similarly also did not occlude because of embolization. The infusion of recombinant human-FVIII (r-hu-FVIII) in FVIII−/− mice normalized the occlusion time to WT values. We also observed thrombus instability in the VWF−/− mice, which was due to lower FVIII levels in these mice since r-huFVIII restored thrombus stability i.e. prevented breaking of the thrombi with large platelet aggregates moving downstream. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF−/− thrombi grew at a slower rate than WT and the venules did not occlude. In transgenic mice lacking the GPIbα extracellular domain, all injured venules occluded. Thus, VWF uses other adhesion receptors besides GPIbα in thrombus growth under venous shear conditions. Our studies document crucial independent roles for VWF and FVIII in experimental thrombosis under venous flow conditions in vivo.

scholarly journals von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2424-2429 ◽  
Author(s):  
Anil K. Chauhan ◽  
Janka Kisucka ◽  
Colin B. Lamb ◽  
Wolfgang Bergmeier ◽  
Denisa D. Wagner
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Initial Contact ◽  
Flow Conditions ◽  
Venous Flow ◽  
Shear Rates ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using gene-targeted mice, we show that in ferric chloride–injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF−/− mice when compared with wild type (WT). We also observed increased embolization in the VWF−/− mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF−/− venules did not occlude. Transgenic platelets lacking the VWF receptor GPIbα extracellular domain showed decreased adhesion to injured veins. But, after a delay, all the injured venules occluded in these transgenic mice. Thus, VWF likely uses other adhesion receptors besides GPIbα in thrombus growth under venous shear conditions. Our studies document crucial roles for VWF and FVIII in experimental thrombosis under venous flow conditions in vivo.

scholarly journals Regulation of plasma von Willebrand factor

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 96 ◽  
Author(s):  
Karl C Desch
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Vascular Wall ◽  
Healthy Human ◽  
Venous Thromboembolic ◽  
Artery Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a central role in the initiation of blood coagulation. Through interactions between its specific functional domains, the vascular wall, coagulation factor VIII, and platelet receptors, VWF maintains hemostasis by binding to platelets and delivering factor VIII to the sites of vascular injury. In the healthy human population, plasma VWF levels vary widely. The important role of VWF is illustrated by individuals at the extremes of the normal distribution of plasma VWF concentrations where individuals with low VWF levels are more likely to present with mucocutaneous bleeding. Conversely, people with high VWF levels are at higher risk for venous thromboembolic disease, stroke, and coronary artery disease. This report will summarize recent advances in our understanding of environmental influences and the genetic control of VWF plasma variation in healthy and symptomatic populations and will also highlight the unanswered questions that are currently driving this field of study.

scholarly journals Direct radioimmune detection in human plasma of the association between factor VIII procoagulant protein and von Willebrand factor, and the interaction of von Willebrand factor-bound procoagulant VIII with platelets

Blood ◽  
1983 ◽  
Vol 61 (6) ◽  
pp. 1163-1173 ◽  
Author(s):  
JL Moake ◽  
MJ Weinstein ◽  
JH Troll ◽  
LE Chute ◽  
NM Colannino
Keyword(s):  
Factor Viii ◽  
Human Plasma ◽  
Von Willebrand Factor ◽  
Sodium Dodecylsulfate ◽  
Coagulation Factors ◽  
Cysteine Protease Inhibitors ◽  
Proteolytic Activation ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The predominant procoagulant factor VIII (VIII:C) form in normal human plasma containing various combinations of anticoagulants and serine/cysteine protease inhibitors is a protein with mol wt 2.6 +/- 0.2 X 10(5). This protein can be detected by 125I-anti-VIII:C Fab binding and gel electrophoresis in the presence and absence of sodium dodecylsulfate (SDS) and is distinct from the subunit of factor VIII/von Willebrand factor (VIII:vWF) multimers. No larger VIII:C form is present in plasma from patients with severe congenital deficiencies of each of the coagulation factors, other than VIII:C. The mol wt approximately 2.6 X 10(5) VIII:C form is, therefore, likely to be the in vivo procoagulant form of VIII:C, rather than a partially proteolyzed, partially activated derivative of a larger precursor. About 60% of this procoagulant mol wt approximately 2.6 X 10(5) VIII:C form in plasma is present in noncovalent complexes with larger VIII:vWF multimers, which attach reversibly to platelet surfaces in the presence of ristocetin. This VIII:vWF-bound protein of mol wt approximately 2.6 X 10(5) may be the plasma procoagulant form of VIII:C which, after proteolytic activation, accelerates the IXa-mediated cleavage and activation of X postulated to occur on platelet surfaces.

scholarly journals Factor VIII-von Willebrand factor requires calcium for facilitation of platelet adherence

Blood ◽  
1984 ◽  
Vol 63 (5) ◽  
pp. 996-103 ◽  
Author(s):  
KS Sakariassen ◽  
M Ottenhof-Rovers ◽  
JJ Sixma
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Divalent Cations ◽  
Platelet Adherence ◽  
Human Arteries ◽  
Platelet Spreading ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

The role of divalent cations in platelet adherence to deendothelialized human arteries in flowing blood was investigated in an annular perfusion chamber. Spreading of platelets on the subendothelium was impaired below 30 microM of free Ca2+ ions (Ca2+). When Ca2+ was replaced by Mg2+, adherence was unchanged in perfusates without exogenous factor VIII-von Willebrand factor (FVIII-vWF), but the ability of FVIII-vWF to support platelet adherence was lost. Binding of FVIII-vWF to the vessel wall was independent of divalent cations, but bound FVIII-vWF was only able to mediate adherence after exposure to Ca2+. Pretreatment of FVIII-vWF with the calcium chelator EGTA (10 mM) resulted in loss of the ability to facilitate platelet adherence, while the ristocetin cofactor activity remained intact. Full restoration of the ability to mediate platelet adherence could only be obtained by prolonged dialysis against Ca2+ in the millimolar range. These data indicate that divalent cations have at least two separate roles to play in supporting platelet adherence: (1) platelet spreading on the subendothelium requires Ca2+ or Mg2+; (2) FVIII-vWF should be exposed to Ca2+ to obtain its optimal biologic activity in supporting platelet adherence.

Adenovirus Induced Thrombocytopenia: The Role of P-Selectin and von Willebrand Factor in Virus- Mediated Platelet Clearance.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 222-222 ◽  
Author(s):  
Maha Othman ◽  
Andrea Labelle ◽  
Ian Mazzetti ◽  
David Lillicrap
Keyword(s):  
Platelet Activation ◽  
Von Willebrand Factor ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Adhesive Proteins ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Acute thrombocytopenia has been consistently reported following IV administration of adenoviral vectors (Ad) but the mechanism responsible for this phenomenon has not been elucidated. Thrombocytopenia appears 24 hours after IV administration of Ad and is vector dose dependent. In this study, we have assessed the potential roles of the adhesive proteins P-selectin and von Willebrand Factor (VWF) on the aggregation and clearance of platelets following virus administration. We have addressed the question of whether the thrombocytopenia is due to a direct effect of the virus on platelets or an indirect effect related to interaction of platelets with other proteins or cells modified by the virus. We assessed platelet count in a group of Balb/c and C57Bl/6 mice over 1 week period following Ad administration and performed a detailed examination of the events within the first 24 h after Ad injection, the period that precedes the appearance of thrombocytopenia. We examined the effect of Ad on expression of the platelet activation marker P-selectin and the formation of platelet leukocyte aggregates (PLA) by means of flowcytometry after incubation of adenovirus with mouse platelets in vitro, and following Ad administration in vivo. To assess the role of VWF in Ad-induced thrombocytopenia we measured plasma VWF levels one hour after injection of Ad. Further investigations involved comparison of platelet counts, platelet activation, and the formation of PLA in a group of VWF KO mice. All studies have been performed with a replication deficient E1/E3-deleted Ad 1x 1011 viral particles/mouse. Our in vitro studies have shown that Ad directly activates mouse platelets as shown by increased expression of P-selectin. The average index of platelet activation for platelets stimulated by Ad was 2519.4 compared to 128.2 for resting platelets (n=5, p<0.02). Flow cytometric analysis of CD41 (platelets) and CD45 (leucocytes) double stained positive events indicated that Ad stimulation induced PLA when compared to the unstimulated samples. Our in vivo studies have confirmed the development of significant thrombocytopenia in both Balb/c as well as C57Bl/6 WT mice (n=8, p=0.00001, n= 6, p=0.002) 24 hours following Ad administration. Significant P-selectin expression was documented in both strains (n=4,p=0.0003; n=3, p=0.0008 respectively) as well as significant PLA one hour following Ad (n=4, p=0.01; n=3, p=0.007). The VWF KO mice showed non-significant thrombocytopenia (n= 6, p=0.063) at 24 hours following Ad, significant P-selectin expression (n=3, p=0.0003), but no significant PLA formation at one hour (n=3 p=0.12) relative to pre-injection levels. Plasma VWF levels were significantly elevated in both Balb/c and C57Bl/6 WT mice one hour following administration of the virus (n= 3, p=0.02; n= 3, p= 0.001). The average plasma VWF levels were 48.1 U/mL at 1h compared to 5.7 U/mL pre injection in Balb /c mice and 85.9 U/mL compared to 6.1 U/mL in C57Bl/6 mice. These studies have shown that Ad can act as an inducer of mouse platelet activation and as a promoter for platelet-leukocyte association both in vitro and in vivo. We have demonstrated a role for Ad in stimulating VWF release from the endothelium, and have shown that VWF has a critical role in platelet activation and clearance following Ad administration. We conclude that P-selectin and VWF proteins are directly involved in interactions between endothelial cells, platelets and leukocytes, a complex interaction that can explain at least in part the mechanisms underlying Ad-mediated thrombocytopenia.

Factor VIII inhibitors: role of von Willebrand factor on the uptake of factor VIII by dendritic cells

Haemophilia ◽  
2007 ◽  
Vol 13 ◽  
pp. 61-64 ◽  
Author(s):  
S. V. KAVERI ◽  
S. DASGUPTA ◽  
S. ANDRE ◽  
A.-M. NAVARRETE ◽  
Y. REPESSÉ ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand ◽  
Willebrand Factor
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